Mycophenolate mofetil in children with steroid/cyclophosphamide-resistant nephrotic syndrome

The purpose of this study was to assess the results of therapy with mycophenolate mofetil (MMF) in children with idiopathic nephrotic syndrome (INS) who were both steroid- and cyclophosphamide-resistant. Treatment lasted a minimum of 6 months, and follow-up data were collected over a 2-year period. The children were divided into two groups: Group 1 (n?=?34) comprised patients who had received cyclosporine A (CsA) before the initiation of MMF therapy; Group 2 (n?=?18) comprised patients who received only MMF. Among the 34 patients of Group 1, complete and partial remission were achieved in seven (20.6%) and 13 patients (38.6%), respectively; there was no response in 14 patients (41.2%). Among the 18 patients in Group 2, complete and partial remission occurred in five (27.8%) and six (33.3%) patients, respectively; there was no response in seven patients (38.9%). Eight patients developed chronic kidney disease. The main side-effects were gastrointestinal complaints (n?=?11, 21%), recurring severe infections (n?=?1, 1.9%), and mild thrombocytopenia/leucopenia (n?=?1, 1.9%). MMF proved to be therapeutically effective in 59.5% of the cases. These beneficial effects need to be confirmed in studies with a long-term follow-up after discontinuation of the treatment. Our statistical analysis of the results of therapy with MMF did not reveal any significant difference between its use alone or following CsA administration.     

New fluorescent 2-phenylindolglyoxylamide derivatives as probes targeting the peripheral-type benzodiazepine receptor: design, synthesis, and biological evaluation

Fluorescent ligands for the peripheral-type benzodiazepine receptor (PBR) featuring the 7-nitrobenz-2-oxa-1,3-diazol-4-yl moiety were synthesized, based on N,N-dialkyl-2-phenylindol-3-ylglyoxylamides, a potent, selective class of PBR ligands previously described by us. All the new ligands are moderately to highly potent at the PBR, with a complete selectivity over the central benzodiazepine receptor. Results from fluorescence microscopy showed that these probes specifically labeled the PBR at the mitochondrial level in C6 glioma cells.     

5-amino-2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1-one: a versatile scaffold to obtain potent and selective A3 adenosine receptor antagonists

Binding assays on human A1, A2A, and A3 adenosine receptors (ARs) and functional studies on A2B ARs revealed that various 2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1,5(6H)-diones VIII, previously reported as ligands at the central benzodiazepine receptor (BzR), possess nanomolar affinity at the A3 AR. Replacement of the amide of VIII with an amidine moiety gave the 5-amino-2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1-ones IX, which maintain a nanomolar potency at the A3 AR with selectivity over the BzR. Insertion of a p-methoxybenzoyl at the 5-amino moiety enhanced A3 AR affinity and selectivity over the A1, A2A, and A2B ARs. The best result of our lead optimization efforts is 9-chloro-5-(4-methoxybenzoyl)amino-2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1-one (23), which displayed a Ki of 1.6 nM at the A3 AR and no significant affinity at the other ARs or the BzR. Docking simulations on selected ligands into a model of the A3 AR allowed us to rationalize the structure-activity relationships of phenyltriazolobenzotriazindiones VIII and aminophenyltriazolobenzotriazinones IX at the molecular level.     

Virological profiles in hepatitis B virus inactive carriers: monthly evaluation in 1-year follow-up study.

STUDY SUBJECT: We longitudinally evaluated the virological behaviour and the hepatitis B virus (HBV) genomic variability in inactive HBV surface antigen (HBsAg) chronic carriers. PATIENTS AND METHODS: Fourteen HBsAg-positive healthy workers (13 inactive carriers and 1 with active HBV infection) were followed up for 12 months by monthly evaluation of aminotransferase, HBV DNA, and IgM anti HBV core antigen (IgM anti-HBc) values. Moreover, HBV serum isolates from each case were amplified, cloned and sequenced to evaluate the presence of the potentially clinical relevant core-promoter and precore mutations. The same technical procedures were used to examine the S gene of isolates from 3 randomly selected inactive carriers and the patients with active HBV infections. RESULTS: Aminotransferase values were constantly normal in all cases. Viremia levels appear to fluctuate widely over time in each individual case, although the HBV DNA remained below 2 x 10(4) copies/ml in all samples. Only four serum samples from two inactive carriers had IgM anti-HBc values higher than the specific cut-off limit of the assay. Either wild type or core-promoter/precore HBV variants or a mixture of them were detected in the inactive carriers. S gene nucleotide homology among the clones from the three inactive carriers and the subject with active infection was 98.9%, 98.3%, 98.1% and 98.2%, respectively. CONCLUSIONS: The degree of suppression of HBV replication in inactive carriers is variable over time, and the entity and quality of HBV variability is comparable between active and inactive carriers.     

Relationship of blood lead levels to blood pressure in exhaust battery storage workers

Several researches has focused the hypothesis that low blood lead levels could be associated with an increased risk of hypertension. To assess the relation between occupational lead exposure and elevated blood pressure a group of 27 workers, age range from 27 to 62 years, mean (SD) 36.52 (+/- 8.16) yr; length of employment mean (DS) 2.97 (+/- 1.67) yr, were recruited as study subjects. The following variables were measured: blood lead concentration (BPb), delta-Aminolevulinic Acid Dehydratase (ALAD) activity, Zinc Protoporphirin (ZPP), creatinine, hematocrit, Body Mass Index (BMI) and Systolic Blood Pressure (SBP) and Diastolic Blood (DBP) Pressure. The results showed that long term occupational exposure was related to a slight increase of systolic and diastolic blood pressure among workers who had been exposed to higher level of lead with respect to workers exposed to lower level of lead. Furthermore, blood lead concentration (BPb) and ZPP resulted higher among workers exposed to higher level of ambient lead, while in the same group of workers ALAD activity resulted more inhibited. The authors concluded long term cumulative lead exposure can significantly increase blood pressure in low level Pb exposed workers.     

Synthesis and benzodiazepine receptor affinity of derivatives of the new tricyclic heteroaromatic system pyrido[3',2':5,6]thiopyrano[4,3-c]pyridazin-3(2H,5H)-one

Derivatives 7-13 of a new tricyclic heteroaromatic system, pyrido[3',2':5,6]thiopyrano[4,3-c]pyridazin-3(2H,5H)-one, were prepared as potential ligands at the benzodiazepine receptor, in view of their structural analogy with potent ligands such as the pyrazoloquinolines of the CGS series II, and especially with the benzothiopyrano[4,3-c]pyridazinones VI. They were obtained starting from the versatile ketones 2,3-dihydrothiopyrano[2,3-b]pyridin-4(4H)-one 1 and the corresponding 7-methyl derivative 2, via condensation with glyoxylic acid, and reaction of the intermediate acid mixtures with hydrazine or substituted phenylhydrazines. When evaluated for their binding affinity at the benzo diazepine receptor in bovine cortical membranes, the target compounds 8-13 displayed an affinity in the micromolar/submicromolar order. A hypothesis is presented to rationalize these results.     

Naphtho[1,2-d]isothiazole acetic acid derivatives as a novel class of selective aldose reductase inhibitors

Acetic acid derivatives of naphtho[1,2-d]isothiazole (NiT) were synthesized and tested as novel aldose reductase (ALR2) inhibitors. The parent compound 11 exhibited a fair inhibitory activity (IC(50) = 10 muM), which was enhanced by 2 orders of magnitude by introducing a second carboxylic group at position 4 (13 and 14: IC(50) = 0.55 and 0.14 muM, respectively). Substitution of the acetic acid function with an apolar group gave inactive (29) or poorly active (25, 26, 30) compounds, thus demonstrating that the 2-acetic group is involved in the enzyme pharmacophoric recognition while the 4-carboxylic moiety has only an accessory role. The potent compounds 11, 13, 14, 26 all proved to be selective for ALR2, since none of them inhibited aldehyde reductase, sorbitol dehydrogenase, or glutathione reductase. The isopropyl ester 31, a prodrug of 14, was found to be effective in preventing cataract development in severely galactosemic rats, when administered as an eyedrop solution. The theoretical binding mode of 13 and 14, obtained by docking simulations into the ALR2 crystal structure, was fully consistent with the structure-activity relationships in the NiT series.     

Electronic Medical Records in a Sub-Specialty Practice: One Asthma Center's Experience

There are numerous known benefits associated with the use of an electronic medical record (EMR). In October of 2004, a pediatric respiratory medicine practice at a major academic institution began the process of implementing an EMR system. Through this process, another benefit was realized, improved coordination between out-patient and in-patient care in relation to asthma education. The process began with the formation of an implementation team. The team consisted of technical as well as clinical experts from various disciplines. Together the team developed templates, decision support tools and standardized patient care letters. The team also determined workflow and provided training on the EMR system. A major benefit associated with EMR implementation was the increase in the number of children who were hospitalized with an asthma exacerbation and received an asthma action plan upon discharge. Prior to the EMR system, 4% received an asthma action plan upon discharge. After implementation of the EMR system, 58% received an asthma action plan upon discharge.