Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants

BACKGROUND: The recurrence of chronic hepatitis B after liver transplantation results in increased risk for graft failure and death of patients. Lamivudine has been shown to be effective in the treatment of chronic hepatitis B, but resistance to this agent is common after prolonged administration. METHODS: One patient with chronic hepatitis B virus (HBV) infection developed resistance to lamivudine after 15 months of treatment. The resistance was confirmed by mutation in the HBV DNA polymerase gene. The patient was treated subsequently with adefovir dipivoxil for 7 months. RESULT: HBV DNA and HBsAg were tested negative, but HBeAb and HBsAb were positive. CONCLUSION: This study provides an evidence that adefovir dipivoxil can be effective in the treatment of lamivudine-resistant HBV mutants.     

Post-transplant infections: single center experience from the developing world.

OBJECTIVE: To describe our experience of post-transplant infections in allogeneic stem cell transplants at the Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan. METHODS: From July 2001 to September 2006, patients with malignant and non-malignant hematological disorders having human leukocyte antigen (HLA)-matched sibling donors were selected for transplant. Pre-transplant infection surveillance was carried out, and strict prophylaxis against infection was observed. After admission to the hospital, patients were kept in protective isolation rooms, equipped with a HEPA filter positive-pressure laminar airflow ventilation system. Bone marrow and/or peripheral blood stem cells were used as the stem cell source. Cyclosporin and prednisolone were used as prophylaxis against graft-versus-host disease (GVHD). The engraftment was monitored with cytogenetic/molecular analysis and change of blood group. Survival was calculated from the date of transplant to death or last follow-up. RESULTS: One hundred and fifty-four patients received allogeneic stem cell transplants from HLA-matched siblings for various hematological disorders at the Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan between July 2001 and September 2006. Indications for transplant included aplastic anemia (n=66), beta-thalassemia major (n=40), chronic myeloid leukemia (n=33), acute leukemia (n=8), and miscellaneous disorders (n=7). One hundred and twenty patients were male and 34 were female. The median age of the patient cohort was 14 years (range 1 1/4-54 years). One hundred and thirty-six patients and 135 donors were cytomegalovirus (CMV) IgG-positive. One hundred and forty patients (90.9%) developed febrile episodes in different phases of post-transplant recovery. Infective organisms were isolated in 150 microbiological culture specimens out of 651 specimens from different sites of infections (23.0% culture positivity). Post-transplant infections were confirmed in 120 patients (77.9%) on the basis of clinical assessment and microbiological, virological, and histopathological examination. Mortality related to infections was 13.0%. Fatal infections included CMV disease (100% mortality, 6/6), disseminated aspergillosis (66.7% mortality, 4/6), pseudomonas septicemia (42.9% mortality, 9/21), and tuberculosis (25% mortality, 1/4). CONCLUSIONS: More than 90% of our patients developed febrile episodes with relatively low culture yield. The majority of infections were treated effectively, however CMV, aspergillosis, and pseudomonas infections remained problematic with high mortality.     

Immunological appraisal of wheat varieties in relation to chapatti-making characteristics

The current research work was conducted to characterize wheat proteins through immunochemical techniques and to find out their relationship with wheat quality traits. The results revealed that wheat variety AARI-11 possessed higher protein content (11.96%), wet gluten (31.39%), dry gluten (9.66%), Pelshenke value (190.52 min), and SDS-Sedimentation value (28.27 ml) than other tested varieties. The chapattis prepared from the wheat variety AARI-11 got significantly higher sensory scores owing to its higher protein contents. The wheat variety AARI-11 also exhibited significantly the highest antibody response against all the assessed protein fractions. The results of the present study suggest that anti-glutenin and anti-high molecular weight glutenin subunits (HMW-GS) antibody response was found positively correlated to the quality characteristics of flours and chapattis. The present study suggests that the use of antibodies response against glutenin and HMW-GS offers good tool for predicting quality and suitability of wheat to chapatti-making quality.     

Immunological appraisal of modified gluten to trim down celiac toxicity

The aim of the present research was to modify wheat gluten by binding methionine to gluten proteins to develop bread for celiac disease (CD) patients. The highest protein content, wet gluten content, dry gluten content and sodium dodecyl sulphate-sedimentation value were shown by the wheat variety AARI-11, therefore, it was selected for gluten modification. The bound methionine to gluten proteins was found increasing along the reaction time as the reaction proceeds and at a maximum near to 60 minutes and then it starts decreasing. The lowest immunoreactivity of the modified gluten was obtained near to 60 min of reaction at pH 10. The results for immunoglobulin A (IgA) index showed that the serum of each patient had positive IgA index to gliadins from unmodified gluten, but just sera of two patients had positive IgA index to gliadins from modified gluten and when these proteins were digested, the sera of no patient's serum had positive IgA reactivity. Among physical characteristics of breads 2 hours after baking, the specific volume of the modified gluten containing bread (4.13 ± 0.14 cm³/g) was lower than the control bread (4.59 ± 0.21 cm³/g). However, bread made with modified gluten had higher specific volumes than other gluten-free breads. Texture of the modified gluten was also affected by modification. Finally, the gluten content in the modified gluten bread was 79 ppm which is under the limits set by the Codex Alimentarius for food with reduced gluten content should have from 20 to 100 ppm. The study concludes that the incorporation of steric immensity into gluten proteins in order to shun immune recognition is the most promising approach to acquire wheat-based products that are tolerated by CD patients.     

The cardiac atria are chambers of active remodeling and dynamic collagen turnover during evolving heart failure

OBJECTIVES: The role of atrial myocytes and extracellular matrix (ECM) changes in atrial chamber remodeling was studied in a canine model of heart failure (HF). BACKGROUND: Cardiac remodeling is a key process mediating the progression of HF. Studies of the structural mechanisms of cardiac remodeling have been limited to the left ventricle. The structural alterations associated with atrial chamber remodeling in evolving HF have not been studied. METHODS: Age- and weight-matched dogs were subjected to right ventricular pacing (240 beats/min) for one and three weeks to produce early and severe HF, respectively. Atrial tissues were assessed for myocyte and ECM changes. RESULTS: Right atrial and left atrial (LA) pressures were significantly increased in early and severe HF. The LA wall tension index was significantly increased at both HF stages by 116% and 443%, respectively. Atrial collagen synthesis and degradation were significantly increased in severe HF. Gelatinase activity was significantly increased at both early and severe stages of HF. Gelatin zymography showed increased matrix metalloproteinases (MMP)-9 with early HF and increased MMP-2 with severe HF. The LA wall tension index was significantly correlated with gelatinase activity and collagen synthesis. Although total atrial collagen content was not changed, disarray of collagen fibers was observed. Atrial myocyte hypertrophy without evidence of apoptosis was also present in severe HF. CONCLUSIONS: There is marked atrial chamber remodeling in canine pacing-induced HF, which is characterized by myocyte hypertrophy and dynamic collagen turnover. Atrial remodeling may contribute to the development of atrial arrhythmias and pulmonary hypertension and could offer a novel therapeutic target.     

Electrooxidation of Pd–Cu NP loaded porous carbon derived from a Cu-MOF

The development of new non-platinum catalysts for alcohol electrooxidation is of utmost importance. In this work, a bimetallic Pd–Cu loaded porous carbon material was first synthesized from a Cu-based metal–organic framework (MOF). The Cu loaded porous carbon was pre-synthesized through calcinating the Cu-based MOF under a N₂ atmosphere. After loading Pd onto the precursor and heating, Pd–Cu loaded porous carbon (Pd–Cu/C) was obtained for alcohol electrooxidation. Electrooxidation experiments revealed that this Pd–Cu bimetal loaded porous carbon assisted steady state electrolysis for alcohol oxidation in alkaline media. Moreover, different alcohols were electrooxidated using the present electrocatalyst for the purposes of discussing the oxidation mechanism. This electrooxidation study of Pd–Cu/C derived from a MOF demonstrates a good understanding of the electrooxidation of different alcohols, and provides useful guidance for developing new electrocatalyst materials for energy conversion and electronic devices.

We have synthesized Pd–Cu NP loaded porous carbon through the direct carbonization of a porous Cu based MOF for efficient electrooxidation.

There is an immediate need to develop direct alcohol fuel cells (DAFCs), which have been proven to be a fine source of energy, which could probably replace fossil fuels use to fulfil global energy demand. As one of the most significant electrocatalytic procedures, the electrooxidation of alcohols is an important process in DAFCs, and has gathered much attention and is attractive, due to high power density output and low pollutant emissions. Generally, Pt based materials are the most common electrocatalysts for alcohol electrooxidation reactions. However, the high cost and limited supply of Pt severely restricts its commercial application. Therefore, the development of new efficient and inexpensive non-platinum alternative materials to Pt-based catalysts is of utmost importance.Metal–organic frameworks (MOF) are assembled from metal ions linked by organic ligands, and are used in catalysis, guest molecule storage/separation, fluorescence, sensors and other devices.^1–3 Due to their highly ordered porous structures and large surface areas, MOFs can also be used as templates/precursors for preparing porous carbon materials through thermal treatment.^4–8 Several MOF derived carbon materials with good electrical conductivity are reported to show effective electrocatalytic performance,⁹ such as in the oxygen evolution reaction (OER),¹⁰ hydrogen evolution reaction (HER),¹¹ and oxygen reduction reaction (ORR).¹² Recently, a zeolitic imidazolate framework ZIF-8 was calcinated in order to prepare porous carbon with both micro- and meso-pores to support Pd electrocatalysts for methanol electrooxidation.¹³ Unfortunately, this could not efficiently limit the use of the noble metal, which gives challenges to scientists for further exploration.It has been demonstrated that the alloying of noble metals with transition metals has been used for the enhancement of catalytic activity and reduction of cost,¹⁴ because of the low cost and relatively high abundance of transition metals. The use of alloyed metal, Pd–M (where M is Cu, Co or Ni), binary electrocatalysts has been reported for effectively improving the catalytic properties.^15–17 For this purpose, introducing a non-noble metal into a noble metal bimetallic system will fulfil the demand for a new catalyst and become an area of interest nowadays. The second metal (such as Cu) will behave as a donor, while Pd has an empty d orbital to accept electrons, and it is assumed that its electronic properties will be more similar to Pt.¹⁸ Therefore, Pd–Cu bimetal loaded porous carbon derived from a Cu-MOF can provide a good electrocatalyst for alcohol oxidation.In this work, as shown in Scheme 1, we have synthesized Cu loaded porous carbon through the direct carbonization of a porous Cu based MOF. After loading Pd onto the precursor and heating, Pd–Cu bimetal loaded porous carbon (Pd–Cu/C) was obtained. Chronoamperometric studies revealed that this Pd–Cu bimetal loaded porous carbon assisted steady state electrolysis for alcohol oxidation in alkaline media. In addition, alcohols with different numbers of carbon atoms (such as ethanol, 1-propanol and 2-propanol) were also investigated for electrooxidation. It is important to note that the effectiveness of this bimetallic NP loaded carbon means that it can serve as a catalyst for the electrooxidation of low-molecular weight alcohols, which probably can be used as energy sources in portable electronic devices.Open in a separate windowScheme 1The preparation procedure for Pd–Cu/C derived from HKUST-1 and PdCl₂: (a) MOF HKUST-1; (b) Cu/C calcinated from HKUST-1; (c) PdCl₂ loaded on Cu/C; and (d) the Pd–Cu/C material.Here, a 3-D MOF, HKUST-1 (also called Cu₃(BTC)₂, BTC = 1,3,5-benzenetricarboxylate), was chosen as the precursor for preparing the Cu/C material, due to the structure having high porosity and it being a rich Cu source. The as-synthesized HKUST-1 was calcinated at 700 °C for 5 h under a N₂ atmosphere, and the Cu/C material was obtained. In addition, the guest species PdCl₂ was loaded onto the calcinated HKUST-1 through immersing the pre-calcinated HKUST-1 into a PdCl₂ ethanolic solution (1 mM) for 2 h (Scheme 1). The PdCl₂ loaded Cu/C (PdCl₂@Cu/C) was heated at 300 °C for 1 h under a N₂ atmosphere. Finally, an alloy of Pd and Cu loaded porous carbon material (Pd–Cu/C) was obtained and characterized through powder XRD, BET and XPS analyses.The PXRD data (Fig. 1a) from as-synthesized HKUST-1 powder and the bimetallic Pd–Cu NP loaded carbon porous material derived from HKUST-1 show that the samples contain bimetallic palladium and copper mostly. The XRD peak appearing at 43.3° corresponds to the (fcc) (111) facet plane of Cu. Due to Pd being dispersed homogenously at a low concentration through the sample, the XRD pattern could not display the obvious peak from Pd. However, inductively coupled plasma emission spectroscopy (ICP) data (Table S1^†) from the sample showed 0.76% Pd and 36.68% Cu, indicating the existence of Pd and Cu. The porosity of Pd–Cu/C was demonstrated through BET data, which shows N₂ adsorption of ∼150 cm³ g⁻¹. The Pd XPS spectrum showed two definite peaks at 335.5 and 341 eV, respectively assigned to 3d_5/2 and 3d_3/2 and matching well with Pd⁰. XPS peaks at 932.4 and 952.1 eV indicate the valence states of Cu ions in the Cu 2p_3/2 and Cu 2p_1/2 orbitals in the Pd–Cu/C material. Cu²⁺ is present in the porous carbon material, with respective peaks at 933.7 eV and 934.4 eV from CuO and Cu(OH)₂, with a prominent satellite observed in the 938–946 eV range. A few Pd²⁺ ions also exist in the sample due the easy oxidation of the surface. The Raman spectrum of Pd–Cu/C (Fig. S4^†) shows typical graphitic carbon. The results of the characterization studies clearly reveal that the nanoparticles have a Pd and Cu bimetallic nature.Open in a separate windowFig. 1(a) XRD data from HKUST-1 and Pd–Cu/C; (b) N₂ sorption isotherms for Pd–Cu/C; and XPS data from (c) Pd and (d) Cu in a sample of Pd–Cu/C.SEM images with EDS (Fig. 2a and b) results show that the sample contained much more copper than palladium, which clearly suggests that the presence of copper in the sample would probably be the reason for the expected electrooxidation of alcohols. It could be possible to replace the use of high-cost Pd or Pt based catalysts. The morphology of the Pd–Cu NPs was further characterized via TEM imaging and TEM element mapping (Fig. 2c, d and S5^†), demonstrating that the nano-sized NPs were dispersed homogeneously. The HR-TEM image in Fig. 2c gives insight into the bimetallic nature of the synthesized nanoparticles, with two noticeable lattice fringes (0.225 nm for Pd(111) and 0.202 nm for Cu(111)). The mean size of the Pd–Cu NPs was 7.38 nm, as shown in Fig. 2d. The homogenous distribution, with well-defined bimetallic Pd–Cu based carbon material, was good for the electrooxidation of alcohols. The electrochemical active surface area (ECSA) for Pd–Cu/C was high compared with commercial Pd/C, which suggested that the synthesized Pd–Cu/C has ample available surface area, mainly because of synergistic effects from the Cu-MOF based carbon material and the morphology of the electrocatalyst.Open in a separate windowFig. 2(a) SEM image of and (b) EDS data from Pd–Cu/C; (c) a TEM image of Pd–Cu NPs in the hybrid carbon material; and (d) the size distribution of the Pd–Cu NPs.In Fig. 3, CV profiles for commercial Pd/C and the presented Pd–Cu/C show two distinct peaks (forward (iF) and backward (iB) peaks) during the oxidation of methanol-containing 1 M KOH solution. The peak at −0.37 V indicates the oxidation of aforementioned carbonaceous species, such as Pd–CO_ads, along with newly formed alcohol adsorbates, following the removal of surface intermediates at lower potentials.¹⁹ For the forward peak potential, a shift in the iF value is observed, mainly because of Cu existing with Pd in the material. This results in the oxidation of poisonous species, such as Pd adsorbed CO, at higher potentials,²⁰ leading to such high activity. ATR-IR (Fig. S7^†) and GC analyses (Fig. S8^†) show the methanol oxidation reaction (MOR) pathway during the formation of the final CO₂ product. The catalytic activity of Pd–Cu/C is found to be ∼13 times higher than commercial Pd/C for methanol oxidation, demonstrating that the presence of Cu with Pd in Pd–Cu based catalysts increases CO oxidation because of a strong binding ability. Cu binds to CO more strongly than Pd, as a result of electronic structure differences,^21,22 thus preventing the electrode from undergoing CO poisoning, a major issue for Pd-based catalysts during the methanol oxidation reaction (MOR). The mechanism of methanol oxidation is shown in the ESI (eqn (8)–(10)).^† The high iF value for Pd–Cu/C can be ascribed to the fast formation of reactive intermediates, such as Pd–CH₂OH, Pd–COOH, Pd–H, Pd–(CHO)_ads, and Pd–(COOH)_ads.^23–25 The removal of these intermediates is necessary for a high current density. Furthermore, formaldehyde (HCHO), formic acid (HCOOH) and CO₂ would be the final products in the MOR.^26,27 Pd–Cu/C has good catalytic activity for the MOR, leading to further investigation into the electrooxidation of different alcohols, such as ethanol, 1-propanol, and 2-propanol (Fig. 4 and Table S2^†).Open in a separate windowFig. 3CV curves from Pd/C and Pd–Cu/C electrocatalysts during CH₃OH (1 M) oxidation in 1 M KOH solution, at a scan rate of 50 mV s⁻¹, at room temperature.Open in a separate windowFig. 4(a) CV curves from: the Pd–Cu/C electrocatalyst for C₁–C₃ aliphatic alcohol (1 M) oxidation in KOH (1 M) solution; and (b) Pd–Cu/C in 1 M EtOH, 1-propanol and 2-propanol at a scan rate of 50 mV s⁻¹ at room temperature.The current densities for different alcohol oxidation processes are summarized in Fig. 4a and b. The normalized iF (calculated using Pd mass) for the MOR (∼4643 mA mg⁻¹) was higher than for three other alcohols, i.e., it was ∼139, ∼94 and ∼26.5 mA mg⁻¹ for ethanol, 1-propanol and 2-propanol, respectively. The iF/iB ratio for methanol is ∼12 times higher than that for ethanol, ∼13 times that for 1-propanol and ∼4 times that for 2-propanol. The reactivity order for Pd–Cu/C is methanol > ethanol > 1-propanol > 2-propanol. 2-Propanol electrooxidation showed a lower current density on a Pd–Cu/C electrode in alkaline medium, although iF/iB is ∼5.4. The negative shift in the onset of the ethanol oxidation reaction (EOR) suggested that a high copper content with very low amount of Pd was suitable for EOR kinetics using a Pd–Cu/C catalyst. The ethoxy (CH₃CO)_ads was strongly adsorbed, and blocked hydrogen absorption/adsorption. The current intensity of iF increased due to the formation of fresh Pd–OH, through stripping carbonaceous residue from the electrode (eqn (11)–(14)^†). In addition, the increased current at high potentials sharply reached the largest value then started to decline, because a PdO layer formed on the electrode, blocking the further adsorption of reactive species.²⁸ ATR-IR spectra (Fig. S9^†) show the presence of CO₂ and CO_ads, whereas bands appear at 1670 cm⁻¹ and 1390 cm⁻¹ because of the formation of acetic acid.²⁹ The Pd–Cu/C electrocatalyst has the potential to oxidize the intermediate to the final product, CO₂, during EOR to some extent; Cu promotes oxidation through increasing the production of OH_ads⁻/H₂O to eliminate the intermediate CH₃CO_ads simultaneously on Pd.³⁰ The stability of Pd–Cu/C in all four alcohols (methanol, ethanol, 1-propanol and 2-propanol) was studied using chronoamperometry at a potential of −0.25 V, as shown in Fig. S2.^† The slow current decay showed that the stability of the Pd–Cu/C electrocatalyst in methanol is best. Comparing the results, the current for methanol oxidation was higher than that for the other three alcohols. However, the oxidation currents from ethanol and 1-propanol were larger than that from 2-propanol. This suggested that Pd–Cu/C is less stable and shows lower anti-poisoning ability during 2-propanol oxidation in an alkaline medium.During this oxidation, 1-propanol oxidizes to propanal first, and its further oxidation results in the formation of a stable product, propanoic acid (Scheme S1^†). 1-Propanol is converted, with its carboxylate as the major product, as verified using ATR-IR (Fig. S10^†). 2-Propanol forms acetone as an intermediate product, leading to the poisoning of the electrode.³¹ ATR-IR spectra (Fig. S11^†) of Pd–Cu/C also confirm that the electrocatalyst follows a dual pathway through acetone and propene intermediates to oxidize to CO₂ finally (Scheme S2^†).^32–34 However, acetone formation is kinetically favored.³⁵ The results show that the location of the –OH group in the alcohol influences the electrooxidation reaction kinetics. In contrast methanol oxidation using Pd–Cu/C has much higher catalytic activity than ethanol, 1-propanol and 2-propanol oxidation, which makes it a good candidate for direct methanol fuel cells.In summary, we have first synthesized a bimetallic Pd–Cu NP loaded porous carbon material from a Cu-based MOF for alcohol electrooxidation. The Cu loaded porous carbon was pre-synthesized by calcinating the Cu-based MOF HKUST-1 under a N₂ atmosphere. Afterwards, Pd–Cu NP loaded porous carbon was obtained for alcohol electrooxidation. Electrooxidation experiments revealed that Pd–Cu/C was suitable for steady state electrolysis for alcohol oxidation in alkaline media. In addition, different alcohols were electrooxidated using the present electrocatalyst to discuss the oxidation mechanism. This electrooxidation study of Pd–Cu/C derived from a MOF offers good understanding into the electrooxidation of different alcohols and it could provide useful guidance for the development of new electrocatalyst materials.     

Multiple fistulae connecting the right coronary artery to the coronary sinus

Right coronary artery to coronary sinus fistula is a rare anomaly. We present a unique case of an adult patient with multiple fistulae from the right coronary artery draining into the coronary sinus near the posterior left atrium-left ventricle junction, first suspected by transthoracic two-dimensional echocardiography. The multiple openings were not seen by any invasive or noninvasive techniques and were noted only at the time of surgery. To our knowledge, this is the first case of multiple fistulae connecting the right coronary artery to the coronary sinus that has been reported in the English literature.