Effects of cigarette smoke, nicotine and cotinine on red blood cell hemolysis and their -SH capacity

BACKGROUND:

Smoking is a leading cause of premature death. Red blood cell (RBC) membrane lipids are rich in polyunsaturated fatty acids; therefore, the effect of oxygen on RBC membranes is more prominent than on other body tissues. The attachment of peroxidants to RBC membranes can result in hemolysis.

OBJECTIVES:

The present study was conducted to assess the sensitivity of RBCs to 2,2′-azo-bis-(2-amidinopropane) dihydrochloride in smokers and nonsmokers. The effect of cigarette smoke, nicotine (1 μg/mL, 1.5 μg/mL and 2.5 μg/mL) and cotinine (1.25 μg/mL, 2.5 μg/mL and 5 μg/mL) on RBC hemolysis was also examined.

RESULTS:

RBC hemolysis in smokers was 21.6% higher than in non-smokers (P<0.05). Cigarette smoke increased 2,2′-azo-bis-(2-amidino-propane) dihydrochloride-induced RBC hemolysis by 281.7%. Nicotine inhibited RBC hemolysis by 36.7% at the highest concentration used, but increased RBC hemolysis at the lower concentrations. Cotinine caused a 13.8% increase in RBC membrane peroxidation at the highest concentration used and its effects were dose-dependent. At their highest concentrations, nicotine and cotinine decreased -SH groups by 50%.

CONCLUSIONS:

The present study confirms the results from previous studies of the oxidative and destructive effects of cigarette smoke, which are detrimental to the health of both active and passive smokers.     

Serum levels of homocysteine in mice with malignant tumours

BACKGROUND:

Oxygen radicals and malondialdehyde (MDA) are tumourigenic. Homocysteine generates oxygen radicals. The possibility exists that hyperhomocysteinemia is a risk factor for cancer.

OBJECTIVE:

To investigate if serum levels of homocysteine and MDA are elevated in mice with malignant tumours.

METHODS:

Levels of serum homocysteine and MDA were estimated in 22 control and 22 tumour-bearing Balb/c mice.

RESULTS:

Serum homocysteine levels in control and tumour-bearing mice were 3.01±0.26 μmol/L and 4.05±0.46 μmol/L, respectively. The serum levels of MDA were 6.23±0.72 nmol/mL and 11.60±1.72 nmol/mL, respectively, in control and tumour-bearing mice.

CONCLUSION:

These results suggest that cancer in mice is associated with an increase in serum levels of homocysteine and the lipid peroxidation product MDA. It is, however, not known if this rise in homocysteine and MDA is due to cancer or if this rise causes cancer.     

Plasma nitric oxide metabolite levels increase during successive exercise stress testing – A link to delayed ischemic preconditioning?

BACKGROUND:

Animal studies have shown that nitric oxide is involved in delayed ischemic preconditioning.

OBJECTIVES:

To determine whether plasma nitrates and nitrites (NO_x⁻, as measure of nitric oxide) are modified by two consecutive effort tests and whether these changes translate into clinical improvement

METHODS:

Twenty-two patients with ischemic heart disease each performed two effort tests at 24-h intervals. Plasma NO_x⁻ level was determined and compared before and after both stress tests. Peak effort, double product at peak effort and maximal ST segment depression were considered clinical endpoints and were compared between the two tests.

RESULTS:

Plasma NO_x⁻increased slightly after the first exercise test compared with pretest value (17.05±1.6 μmol/mL versus 15.38±1.4 μmol/mL). In turn, after the second test there was a significant rise in NO_x⁻ level (23.65±2.2 μmol/mL versus 15.10±1.3 μmol/mL, P<0.03). The pretest values were almost identical between the two tests. Peak effort and double product at peak effort remained unchanged between the two tests. Although ischemic stress was the same, ST depression was significantly lower (P<0.01) for the second test (0.85±0.06 mm versus 1.73±0.16 mm).

CONCLUSION:

Our study shows an increased plasma NO_x⁻level after the second of two consecutive exercise stress tests at 24-h intervals, along with a decrease of electrocardiographic consequences of approximately the same ischemic stress. These findings are consistent with experimental data in animals, which point to nitric oxide as a trigger and effector of ischemic preconditioning.     

Effects of a short course of inhaled corticosteroids in noneosinophilic asthmatic subjects

BACKGROUND:

Noneosinophilic asthma has been regarded as a distinct phenotype characterized by a poor response to inhaled corticosteroids (ICS).

OBJECTIVE:

To determine whether noneosinophilic, steroid-naive asthmatic subjects show an improvement in asthma control, asthma symptoms and spirometry after four weeks of treatment with ICS, and whether they further benefit from the addition of a long-acting beta-2 agonists to ICS.

METHODS:

A randomized, double-blind, placebo-controlled, multicentre study comparing the efficacy of placebo versus inhaled fluticasone propionate 250 μg twice daily for four weeks in mildly uncontrolled, steroid-naive asthmatic subjects with a sputum eosinophil count ≤2%. This was followed by an open-label, four-week treatment period with fluticasone propionate 250 μg/salmeterol 50 μg, twice daily for all subjects.

RESULTS:

After four weeks of double-blind treatment, there was a statistically significant and clinically relevant improvement in the mean (± SD) Asthma Control Questionnaire score in the ICS-treated group (n=6) (decrease of 1.0±0.5) compared with the placebo group (n=6) (decrease of 0.09±0.4) (P=0.008). Forced expiratory volume in 1 s declined in the placebo group (−0.2±0.2 L) and did not change in the ICS group (0.04±0.1 L) after four weeks of treatment (P=0.02). The open-label treatment with fluticasone propionate 250 μg/salmeterol 50 μg did not produce additional improvements in those who were previously treated for four weeks with inhaled fluticasone alone.

CONCLUSION:

A clinically important and statistically significant response to ICS was observed in mildly uncontrolled noneosinophilic asthmatic subjects.     

Ventricular pacing thresholds following high-energy implantable cardioverter defibrillator shocks in integrated bipolar defibrillation systems

BACKGROUND:

Increased ventricular pacing thresholds have been observed following monophasic implantable cardioverter defibrillator (ICD) shocks.

AIM:

To examine changes following high-energy biphasic shocks delivered by integrated bipolar ICD systems.

METHOD:

Ten episodes of ventricular fibrillation (VF) were induced at 10 min intervals in nine pigs with integrated ICD systems. After 10 s of each episode of VF, a 40 J biphasic shock was delivered, which successfully terminated VF (a total of 10 shocks). The bipolar pacing threshold at the right ventricular apex was measured before each shock and at 1 min intervals after each shock.

RESULTS:

The mean pacing threshold was 0.029±0.059 μJ before the first shock and gradually increased to 0.14±0.10 μJ after the 10th shock.

CONCLUSION:

It may be necessary to pace at a high-voltage output following biphasic shocks delivered by integrated bipolar ICD systems.     

Low-molecular-weight proteins as prognostic markers in idiopathic membranous nephropathy

Summary

Background

Accurate prediction of prognosis in idiopathic membranous nephropathy (iMN) allows restriction of immunosuppressive therapy to patients at high risk for ESRD. Here we re-evaluate urinary low-molecular-weight proteins as prognostic markers and explore causes of misclassification.

Design, setting, participants, & measurements

In a cohort of 129 patients with serum creatinine concentration <135 μmol/L and proteinuria ≥3.0 g/10 mmol, urinary α1- (uα1m) and β2-microglobulin (uβ2m) excretion rate was determined. Urinary α1m and uβ2m-creatinine ratio was also obtained. We defined progression as a rise in serum creatinine ≥50% or ≥25% and an absolute level ≥135 μmol/L.

Results

Median survival time was 25 months, and 47% of patients showed progression. The area under the receiver operating characteristic curve for uβ2m was 0.81 (95% CI: 0.73 to 0.89). Using a threshold value of 1.0 μg/min, sensitivity and specificity were 73% and 75%, respectively. Similar accuracy was observed for the uβ2m-creatinine ratio with sensitivity and specificity of 75% and 73%, respectively, at a threshold of 1.0 μg/10 mmol creatinine. Similar accuracy was found for uα1m and uα1m-creatinine ratio. Blood Pressure and cholesterol contributed to misclassification. Repeated measurements improved accuracy in patients with persistent proteinuria: the positive predictive value of uβ2m increased from 72% to 89% and the negative predictive value from 76% to 100%.

Conclusions

Urinary excretion of uα2m and uβ2m predict prognosis in iMN. A spot urine sample can be used instead of a timed sample. A repeated measurement after 6 to 12 months increases prognostic accuracy.     

Emergence of penicillin-resistant Streptococcus pneumoniae in southern Ontario, 1993�C94

Objective:

To determine the prevalence of resistance of Streptococcus pneumoniae to penicillin and other antimicrobial agents in metropolitan Toronto.

Design:

Consecutive pneumococcal isolates from different patients were obtained from two private community-based laboratories and from patients assessed in the emergency department of a tertiary-care teaching hospital in Toronto, Ontario between June and December 1993, and between March and October 1994. In vitro susceptibility testing was done by broth microdilution in accordance with National Committee for Clinical Laboratory Standards guidelines.

Results:

Twenty (7.3±3.1%) of 274 pneumococcal isolates were resistant to penicillin; six (30%) isolates had high-level resistance (minimal inhibitory concentration [mic] 2.0 μg/mL or greater); and 14 isolates had intermediate resistance (mic 0.1 to 1.0 μg/mL). Penicillin-resistant strains were also frequently resistant to tetracycline (55%), cotrimoxazole (50%), erythromycin (40%) and cefuroxime (35%). Resistant strains comprised several serotypes: 19F (six isolates), 9V (three), 23F (three), and one each of 6A, 6B, 14, and 19A; four isolates were nontypeable.

Conclusions:

There has been a recent emergence of penicillin-resistant S pneumoniae in southern Ontario. National and regional surveillance is warranted to determine the extent of the problem elsewhere in Canada.     

Intracellular energetic units in healthy and diseased hearts

BACKGROUND:

The present review examines the role of intra-cellular compartmentation of energy metabolism in vivo.

OBJECTIVE:

To compare the kinetics of the activation of mitochondrial respiration in skinned cardiac fibres by exogenous and endogenous adenine nucleotides in dependence of the modulation of cellular structure and contraction.

METHODS:

Saponin-permeabilized cardiac fibres or cells were analyzed using oxygraphy and confocal microscopy.

RESULTS:

Mitochondria respiration in fibres or cells was upregulated by cumulative additions of ADP to the medium with an apparent K_m of 200 μM to 300 μM. When respiration was stimulated by endogenous ADP produced by intracellular ATPases, a near maximum respiration rate was achieved at an ADP concentration of less than 20 μM in the medium. A powerful ADP-consuming system, consisting of pyruvate kinase and phosphoenolpyruvate, that totally suppressed the activation of respiration by exogenous ADP, failed to abolish the stimulation of respiration by endogenous ADP, but did inhibit respiration after the cells were treated with trypsin. The addition of up to 4 μM of free Ca²⁺ to the actively respiring fibres resulted in reversible hypercontraction associated with a decreased apparent K_m for exogenous ADP. These changes were fully abolished in fibres after the removal of myosin by KCl treatment.

CONCLUSIONS:

Mitochondria and ATPases, together with cytoskeletal proteins that establish the structural links between mitochondria and sarcomeres, form complexes – intracellular energetic units (ICEUs) – in cardiac cells. Within the ICEUs, the mitochondria and ATPases interact via specialized energy transfer systems, such as the creatine kinase- and adenylate kinase-phosphotransfer networks, and direct ATP channelling. Disintegration of the structure and function of ICEUs results in dyscompartmentation of adenine nucleotides and may represent a basis for cardiac diseases.     

Effects of chromium malate on glycometabolism,glycometabolism‐related enzyme levels and lipid metabolism in type 2 diabetic rats: A dose–response and curative effects study

Aims/Introduction

The present study was designed to evaluate the effect of chromium malate on glycometabolism, glycometabolism-related enzyme levels and lipid metabolism in type 2 diabetic rats, and dose–response and curative effects.

Materials and Methods

The model of type 2 diabetes rats was developed, and daily treatment with chromium malate was given for 4 weeks. A rat enzyme-linked immunosorbent assay kit was used to assay glycometabolism, glycometabolism-related enzyme levels and lipid metabolism changes.

Results

The results showed that the antihyperglycemic activity increased with administration of chromium malate in a dose–dependent manner. The serum insulin level, insulin resistance index and C-peptide level of the chromium malate groups at a dose of 17.5, 20.0 and 20.8 μg chromium/kg bodyweight were significantly lower than that of the model, chromium trichloride and chromium picolinate groups. The hepatic glycogen, glucose-6-phosphate dehydrogenase and glucokinase levels of the chromium malate groups at a dose of 17.5, 20.0 and 20.8 μg chromium/kg bodyweight were significantly higher than that of the model, chromium trichloride and chromium picolinate groups. Chromium malate at a dose of 20.0 and 20.8 μg chromium/kg bodyweight significantly changed the total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides levels compared with the chromium trichloride and chromium picolinate groups.

Conclusions

The results showed that chromium malate exhibits greater benefits in treating type 2 diabetes, and the curative effect of chromium malate is superior to chromium trichloride and chromium picolinate.     

The Impact of Postgraduate Training on USMLE? Step 3? and its Computer-Based Case Simulation Component

BACKGROUND

The United States Medical Licensing Examination® (USMLE®) Step 3® examination is a computer-based examination composed of multiple choice questions (MCQ) and computer-based case simulations (CCS). The CCS portion of Step 3 is unique in that examinees are exposed to interactive patient-care simulations.

OBJECTIVE

The purpose of the following study is to investigate whether the type and length of examinees’ postgraduate training impacts performance on the CCS component of Step 3, consistent with previous research on overall Step 3 performance.

DESIGN

Retrospective cohort study

PARTICIPANTS

Medical school graduates from U.S. and Canadian institutions completing Step 3 for the first time between March 2007 and December 2009 (n = 40,588).

METHODS

Post-graduate training was classified as either broadly focused for general areas of medicine (e.g. pediatrics) or narrowly focused for specific areas of medicine (e.g. radiology). A three-way between-subjects MANOVA was utilized to test for main and interaction effects on Step 3 and CCS scores between the demographic characteristics of the sample and type of residency. Additionally, to examine the impact of postgraduate training, CCS scores were regressed on Step 1 and Step 2 Clinical Knowledge (CK) scores. Residuals from the resulting regressions were plotted.

RESULTS

There was a significant difference in CCS scores between broadly focused (μ = 216, σ = 17) and narrowly focused (μ=211, σ = 16) residencies (p < 0.001). Examinees in broadly focused residencies performed better overall and as length of training increased, compared to examinees in narrowly focused residencies. Predictors of Step 1 and Step 2 CK explained 55% of overall Step 3 variability and 9% of CCS score variability.

CONCLUSIONS

Factors influencing performance on the CCS component may be similar to those affecting Step 3 overall. Findings are supportive of the validity of the Step 3 program and may be useful to program directors and residents in considering readiness to take this examination.KEY WORDS: USMLE, Step 3, CCS, postgraduate training, graduate medical education     

Imbalanced globin chain synthesis determines erythroid cell pathology in thalassemic mice

Background

β-thalassemia occurs from the imbalanced globin chain synthesis due to the absence or inadequate β-globin chain production. The excessive unbound α-globin chains precipitate in erythroid precursors and mature red blood cells leading to ineffective erythropoiesis and hemolysis.

Design and Methods

In vitro globin chain synthesis in reticulocytes from different types of thalassemic mice was performed. The effect of imbalanced globin chain synthesis was assessed from changes of red blood cell properties including increased numbers of red blood cells vesicles and apoptotic red blood cells, increased reactive oxygen species and decreased red blood cell survival.

Results

The α/β-globin chain ratio in β^IVSII-654-thalassemic mice, 1.26±0.03, was significantly higher than that of wild type mice, 0.96±0.05. The thalassemic mice show abnormal hematologic data and defective red blood cell properties. These values were improved significantly in doubly heterozygous thalassemic mice harboring 4 copies of human β^E-globin transgene, with a more balanced globin chain synthesis, 0.92±0.05. Moreover, transgenic mice harboring 8 extra copies of the human β^E-globin transgene showed inversely imbalanced α/β-globin synthesis ratio, 0.83±0.01, that resulted in a mild β-thalassemia phenotype due to the excessive β-globin chains. The degree of ineffective erythropoiesis also correlated with the degree of imbalanced globin chain synthesis. Bone marrow and splenic erythroid precursor cells of β^IVSII-654-thalassemic mice showed increased phosphatidylserine exposure in basophilic and polychromatophilic stages, which was restored to the normal level in doubly heterozygous mice.

Conclusions

Imbalanced α/β-globin chain as a consequence of either reduction or enhancement of β-globin chain synthesis can cause abnormal red blood cell properties in mouse models.     

A randomized controlled trial of two schedules of hepatitis B vaccination in predialysed chronic renal failure patients

Background

Patients with chronic renal disease should be vaccinated as soon as dialysis is forestalled, and this could improve the seroconversion of hepatitis B vaccination.

Objectives

In this study, we aimed to compare seroconversion and immune response rates using 4 doses of 40 μg and 3 doses of 20 μg Euvax B recombinant Hepatitis B surface Antigen (HBs Ag) vaccine administered to predialysis patients with chronic kidney disease (CKD).

Patients and Methods

In an open, randomized clinical trial, we compared seroconversion rates in 51 predialysis patients with mild and moderate chronic renal failure who received either 4 doses of 40 μg or 3 doses of 20 μg of Euvax B recombinant hepatitis B vaccine administered at 0, 1, 2, 6 and 0, 1, 6 months, respectively.

Results

Differences in seroconversion rates after 4 doses of 40 μg (80.88%) compared to 3 doses of 20 μg (92%) were not significant (P = 0.4124). The mean HBs antibody level after 4 doses of 40 μg at 0, 1, 2, and 6 months (182.2 ± 286.7) was significantly higher than that after 3 doses of 40 μg at 0,1, and 6 months (96.9 ± 192.1) (P = 0.004). Seroconversion after 4 doses of 40 μg (80.8%) was also significantly higher than that after 3 doses of 40 μg (77%) (P = 0.004). Multivariable analysis showed that none of the variables contributed to seroconversion.

Conclusions

We found that 4 doses of 40 μg did not lead to significantly more seroconversion than 3 doses of 20 μg.     

Renal effects of long-term treatment with 5-aminosalicylic acid

BACKGROUND:

A number of case reports link the use of 5-aminosalicylic acid (5-ASA) to interstitial nephritis in patients with inflammatory bowel disease (IBD).

OBJECTIVE:

To investigate whether the long-term use of 5-ASA has harmful effects on renal function in patients with IBD.

METHODS:

A retrospective analysis of 171 consecutive outpatients with Crohn’s disease or ulcerative colitis was conducted. Serum creati-nine levels and body weight were measured before and after treatment to calculate the creatinine clearance (CrCl) rate.

RESULTS:

In 171 patients (93 women, 78 men), the mean (± SD) dose of 5-ASA was 3.65±0.85 g/day with a cumulative dose of 11±7.7 kg over an interval of 8.4±5.9 years. Serum creatinine concentrations increased from 76.8 μmol/L to 88.7 μmol/L (n=171; P<0.0001) and the CrCl rate fell significantly from 104.6 mL/min to 93.1 mL/min (n=81; P<0.0001). There was one case of interstitial nephritis reported. Treatment groups included mesalamine (74.3%), sulfasalazine (15.2%) and combination (sulfalsalazine/mesalamine [10.5%]) with treatment durations of 7.2±4.5, 12.3±8.7 and 11.2±6.7 years, respectively. The duration of treatment was the most important covariate for change in CrCl and when analyzed by treatment group, those treated with sulfasazine had a strong correlation (r=−0.54, P=0.0145), while nonsignificant in the mesalamine group (r=0.06, P=0.7017). The decline in CrCl was negatively correlated with the pretreatment CrCl rate (r=−0.34; P=0.0024) and positively correlated with the mean daily dose of 5-ASA (r=0.32; P=0.0034).

CONCLUSION:

The present study is the first to demonstrate a significant dose- and treatment duration-dependant decline in CrCl. The risks need to be further evaluated because 5-ASA is widely used for long-term maintenance therapy in patients with IBD.     

Prevention of contrast-induced nephropathy: A randomized controlled trial of sodium bicarbonate and N-acetylcysteine

BACKGROUND:

Contrast-induced nephropathy (CIN) continues to be a common cause of acute renal failure in high-risk patients undergoing radiocontrast studies. However, there is still a lack of consensus regarding the most effective measures to prevent CIN.

METHODS:

One hundred eighteen patients with diabetes mellitus and/or renal insufficiency, scheduled for coronary angiography or intervention, were randomly assigned to one of four treatment groups: intravenous (IV) 0.9% NaCl alone, IV 0.9% NaCl plus N-acetylcysteine (NAC), IV 0.9% sodium bicarbonate (NaHCO₃) alone or IV 0.9% NaHCO₃ plus NAC. All patients received IV hydration as a preprocedure bolus and as maintenance. Iso-osmolar contrast was used in all patients. CIN was defined as an increase of greater than 25% in the serum creatinine concentration from baseline to 72 h.

RESULTS:

The overall incidence of CIN was 6%. There was no statistically significant difference in the incidence of CIN among the groups. There was a CIN incidence of 7% in the NaCl only group, 5% in the NaCl/NAC group, 11% in the NaHCO₃ only group and 4% in the NaHCO₃/NAC group (P=0.86). The maximum increase in serum creatinine was 14.14±12.38 μmol/L in the NaHCO₃ group, 10.60±29.14 μmol/L in the NaCl only group, 9.72±13.26 μmol/L in the NaCl/NAC group and 0.177±15.91 μmol/L for the NaHCO₃/NAC group (P=0.0792).

CONCLUSION:

CIN in high-risk patients may be effectively minimized solely through the use of an aggressive hydration protocol and an iso-osmolar contrast agent. The addition of NaHCO₃ and/or NAC did not have an effect on the incidence of CIN.     

Bioluminescence imaging of glucose in tissue surrounding polyurethane and glucose sensor implants

Background

The bioluminescence technique was used to quantify the local glucose concentration in the tissue surrounding subcutaneously implanted polyurethane material and surrounding glucose sensors. In addition, some implants were coated with a single layer of adipose-derived stromal cells (ASCs) because these cells improve the wound-healing response around biomaterials.

Methods

Control and ASC-coated implants were implanted subcutaneously in rats for 1 or 8 weeks (polyurethane) or for 1 week only (glucose sensors). Tissue biopsies adjacent to the implant were immediately frozen at the time of explant. Cryosections were assayed for glucose concentration profile using the bioluminescence technique.

Results

For the polyurethane samples, no significant differences in glucose concentration within 100 μm of the implant surface were found between bare and ASC-coated implants at 1 or 8 weeks. A glucose concentration gradient was demonstrated around the glucose sensors. For all sensors, the minimum glucose concentration of approximately 4 mM was found at the implant surface and increased with distance from the sensor surface until the glucose concentration peaked at approximately 7 mM at 100 μm. Then the glucose concentration decreased to 5.5–6.5 mM more than 100 μmm from the surface.

Conclusions

The ASC attachment to polyurethane and to glucose sensors did not change the glucose profiles in the tissue surrounding the implants. Although most glucose sensors incorporate a diffusion barrier to reduce the gradient of glucose and oxygen in the tissue, it is typically assumed that there is no steep glucose gradient around the sensors. However, a glucose gradient was observed around the sensors. A more complete understanding of glucose transport and concentration gradients around sensors is critical.     

The Efficacy and Safety of Peginterferon-α-2a in Korean Patients with Chronic Hepatitis B: A Multicenter Study Conducted in a Real Clinical Setting

Background/Aims

Genotype C is the principal type of hepatitis B virus (HBV) in Koreans and is associated with poor prognosis for peginterferon α-2a therapy. The efficacy of and compliance to peginterferon α-2a therapy were investigated in Koreans with hepatitis B in a real clinical setting.

Methods

Hepatitis B patients treated with peginterferon α-2a from 2008 to 2011 at four university hospitals were consecutively enrolled.

Results

Eighty-eight patients were enrolled; 67 were hepatitis B e antigen (HBeAg)-positive. The mean treatment period was 36.1±15.2 weeks. In 26.1% of patients, treatment was discontinued due to insufficient antiviral effects and adverse events. At 24 weeks after treatment, 10/42 (23.8%) HBeAg-positive patients achieved both HBV DNA suppression to <2,000 IU/mL and HBeAg loss/seroconversion. For HBeAg-negative patients, 10/13 (76.9%) achieved HBV DNA suppression to <2,000 IU/mL at 24 weeks after treatment. During the follow-up period, 15 (30.6%) of the 49 patients who achieved HBV DNA suppression to 2,000 IU/mL developed a breakthrough HBV DNA level of >2×10⁶ IU/mL.

Conclusions

Peginterferon α-2a therapy in Koreans with hepatitis B in a real clinical setting resulted in a lower virologic response, as compared to Western individuals, but a favorable durability. There is a need to reduce the high rate of premature discontinuation compared to the controlled studies.     

The anti-cancer drug, phenoxodiol, kills primary myeloid and lymphoid leukemic blasts and rapidly proliferating T cells

Background

The redox-active isoflavene anti-cancer drug, phenoxodiol, has previously been shown to inhibit plasma membrane electron transport and cell proliferation and promote apoptosis in a range of cancer cell lines and in anti-CD3/anti-CD28-activated murine splenocytes but not in non-transformed WI-38 cells and human umbilical vein endothelial cells.

Design and Methods

We determined the effects of phenoxodiol on plasma membrane electron transport, MTT responses and viability of activated and resting human T cells. In addition, we evaluated the effect of phenoxodiol on the viability of leukemic cell lines and primary myeloid and lymphoid leukemic blasts.

Results

We demonstrated that phenoxodiol inhibited plasma membrane electron transport and cell proliferation (IC₅₀ 46 μM and 5.4 μM, respectively) and promoted apoptosis of rapidly proliferating human T cells but did not affect resting T cells. Phenoxodiol also induced apoptosis in T cells stimulated in HLA-mismatched allogeneic mixed lymphocyte reactions. Conversely, non-proliferating T cells in the mixed lymphocyte reaction remained viable and could be restimulated in a third party mixed lymphocyte reaction, in the absence of phenoxodiol. In addition, we demonstrated that leukemic blasts from patients with primary acute myeloid leukemia (n=22) and acute lymphocytic leukemia (n=8) were sensitive to phenoxodiol. The lymphocytic leukemic blasts were more sensitive than the myeloid leukemic blasts to 10 μM phenoxodiol exposure for 24h (viability of 23±4% and 64±5%, respectively, p=0.0002).

Conclusions

The ability of phenoxodiol to kill rapidly proliferating lymphocytes makes this drug a promising candidate for the treatment of pathologically-activated lymphocytes such as those in acute lymphoid leukemia, or diseases driven by T-cell proliferation such as auto-immune diseases and graft-versus-host disease.     

Vitamin K1 supplementation to improve the stability of anticoagulation therapy with vitamin K antagonists: a dose-finding study

Background

Poor anticoagulant stability in patients using vitamin K antagonists is a risk factor for both bleeding and thrombosis. In previous studies supplementation with low dose vitamin K₁ was shown to improve the stability of anticoagulant control. We set up a study to confirm earlier reports and to determine the optimal daily dose of vitamin K₁ in preparation of a large study with clinical endpoints.

Design and Methods

Four hundred patients from two anticoagulation clinics starting with vitamin K antagonists, independently of a possible history of instable anticoagulation, were randomized to receive either placebo or 100, 150 or 200 μg of vitamin K₁ together with their treatment with vitamin K antagonists. The treatment was administered for 6 to 12 months. Anticoagulation stability, expressed as the percentage of time that the International Normalized Ratio was within the therapeutic range, was compared between the groups.

Results

After adjustment for age, sex, vitamin K antagonist used, anticoagulation clinic and interacting drugs as confounding factors the difference in percentage of time with the International Normalized Ratio within the therapeutic range between the placebo group and the vitamin K₁ groups was 2.1% (95% CI: −3.2% – 7.4%) for the group taking 100 μg, 2.7% (95% CI: −2.3% –7.6%) for the group taking 150 μg and 0.9% (95% CI: −4.5% – 6.3%) for the group taking 200 μg vitamin K₁ group, in favor of the vitamin K₁ groups. The patients from both the 100 μg group and the 150 μg group had a 2-fold higher chance of reaching at least 85% of time with the International Normalized Ratio within the therapeutic range. There were no differences in thromboembolic or hemorrhagic complications between the groups.

Conclusions

In patients starting vitamin K antagonists, supplementation with low dose vitamin K₁ resulted in an improvement of time that anticoagulation was within the therapeutic range. Differences between doses were, however, small and the improvement is unlikely to be of clinical relevance. For future studies we recommend selecting only patients with instable anticoagulant control. (This study was registered at www.isrctn.org as ISRCTN37109430)     

Platelet gel in oral and maxillofacial surgery: a single-centre experience

Background

Platelet gel is a blood product intended for non-transfusion, therapeutic purposes; it is produced by combining platelet concentrate with cryoprecipitate. Platelet gel stimulates tissue growth and is a key player in tissue regeneration. As an allogeneic product, platelet gel is obtained from the blood of a common type O blood donor, with a platelet count >200×10³/μL. Most of the beneficial effects of this product are due to the numerous growth factors (PDGF, TGF-β, IGF-1 and IGF-2, EGF, VEGF and FGF) contained in the alpha-granules of platelets. The aim of this study was to confirm that platelet gel is a valuable aid for the surgical repair of alveolar bone loss.

Materials and methods

Our study was carried out on 87 patients with inflammatory or dysembryoplastic osteolytic lesions >2 cm in diameter in jaw bones. For most patients the platelet gel was collected into a 450 mL bag and kept frozen at −40 °C until, whereas for a small group of patients the gel was prepared and activated in the sterile field of the operating theatre.

Results

All of our patients reported a decrease in painful symptoms immediately after surgery. Follow-up showed considerable acceleration of the healing processes in soft tissues and faster bone regeneration.

Conclusion

Multicentre studies are needed in order to standardise the methods for producing platelet gel and the clinical use of this product. Furthermore, for research purposes in vitro studies are needed to increase knowledge on the functional network and platelet growth factors and also to investigate the biochemical and molecular mechanisms involved.     

Comparison of adverse effects related to pegylated interferon-based therapy for patients with chronic hepatitis B and chronic hepatitis C in Taiwan

Purpose

Pegylated interferon (Peg-IFN)-based therapy is effective in treating chronic hepatitis B (CHB) and C (CHC) but frequently induces adverse events (AEs). This study was conducted to compare the incidence of Peg-IFN-based therapy-associated AEs in Taiwanese patients with CHB and CHC.

Methods

Fifty-six patients with CHB and 103 age-, sex- and treatment duration-matched patients with CHC were enrolled. Patients with CHB were treated with Peg-IFN-α-2a 180 μg/week for 24 weeks (HBeAg⁺, n = 31) or 48 weeks (HBeAg⁻, n = 25); patients with CHC were treated with Peg-IFN-α-2a 180 μg/week plus ribavirin 1,000–1,200 mg/day for 24 weeks (genotype 2/3, n = 57) or 48 weeks (genotype 1, n = 46).

Results

Significantly higher incidences of Peg-IFN-related AEs, especially neuropsychiatric symptoms, and ribavirin-associated skin manifestations were observed in patients with CHC compared with those with CHB, with either the 24- or 48-week regimen. Frequencies of laboratory abnormalities, except for anemia, were comparable in both groups. Neither group showed overt hepatic decompensation. Frequency of dose reduction was similar between the groups. Substantially higher rates of early termination and severe AEs were observed in patients with CHC.

Conclusions

Patients with CHB treated with Peg-IFN had fewer AEs than patients with CHC treated with Peg-IFN/ribavirin. All patients were treated safely.