New fixed-dose once-a-day starting regimens: interview with Cal Cohen, M.D. Interview by John S. James

A leading AIDS physician looks at the advantages and disadvantages of once-a day treatment with two new fixed-dose combinations of previously approved drugs, for patients who are first starting antiretrovirals.     

Weekend treatment interruptions for certain well-controlled patients: interview with Cal Cohen, M.D. Interview by John S. James

Dr. Cohen and others at the Community Research Initiative are studying a schedule of five days on certain antiretroviral regimens and two days off, for certain patients whose virus is well suppressed. The goal is to reduce side effects and cost, and to make the regimens easier to take. We asked about the results so far.     

Nail disease due to Scytalidium in Martinique (French West Indies)

INTRODUCTION: Scytalidium is an endemic mold in tropical and subtropial areas. Our purpose was to study the prevalence and clinical and epidemiological features of onychomycoses due to Scytalidium in Martinique (French West Indies). PATIENTS AND METHODS: We performed a prospective study on 106 patients (46 men and 60 women) with clinical onychomycosis, in the dermatological department of the Centre Hospitalier Universitaire of Fort-de-France. All patients underwent mycological sampling and were divided into two groups depending on the presence or not of Scytalidium. Age, sex, localization, clinical aspects, time of duration and environmental factors (place of residence, garden, animals, bare foot walk, immunodepression) were compared between the two groups using chi2, Fisher and Student's t test. Ten control volonteers without clinical onycomycosis underwent mycological sampling. RESULTS: Onychomycosis due to scytalidium represented 42 p. 100 of patients (Scytalidium hyalinum in 91 p. 100 of cases) and 56 p. 100 after elimination of patients with negative results. Medium age was significantly higher in Scytalidium group (62 versus 54 years; p<0.02). Toe nail was involved in 95 p. 100 of patients (big toe nail in 77 p. 100). Sole involvement was more frequent in Scytalidium group (47 p. 100 versus 14 p. 100; p<0.001). Sampling of controls showed scytalidium in one case. DISCUSSION: Our study confirmed the endemicity of Scytalidium hyalinum in Martinique and the frequence of sole involvement. Presence of Scytalidium without clinical features in one control is of epidemiological interest, and may explain the frequence of the disease.     

The respective N-hydroxypyrazole analogues of the classical glutamate receptor ligands ibotenic acid and (RS)-2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid

We have determined the pharmacological activity of N-hydroxypyrazole analogues (3a and 4a) of the classical glutamate receptor ligands ibotenic acid and (RS)-2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid (AMAA), as well as substituted derivatives of these two compounds. The pharmacological profile of 3a is closer to that of thioibotenic acid rather than ibotenic acid, while 4a is a selective N-methyl-D-aspartic acid (NMDA) receptor agonist. Ring substitution of 3a and 4a leads to NMDA receptor antagonists. Whereas efficacy of 3a derivatives at mglu2 receptor decreases from agonism via partial agonism to antagonism with increasing substituent size, substitution abolishes affinity for mglu1 and mglu4 receptors. Ligand- and receptor-based modelling approaches assist in explaining these pharmacological trends among the metabotropic receptors and suggest a mechanism of partial agonism at mglu2 receptor similar to that proposed for the GluR2 glutamate receptor.     

Stability of the distribution of spines containing drebrin A in the sensory cortex layer I of mice expressing mutated APP and PS1 genes

Post-mortem cortices from patients diagnosed with Alzheimer's disease (AD) exhibit reduced levels of drebrin, an F-actin binding protein of dendritic spines and shafts. We used a mouse model of familial AD (FAD) to determine whether the density of cortical spines engaged in asymmetric (presumably excitatory) synapses and containing drebrin A is reduced and if so, whether this occurs prior to the emergence of beta amyloid deposits, when only soluble beta amyloid (Abeta) is present. Quantitative electron microscopic immunocytochemistry revealed that by 6 months, the proportion of postsynaptic spines with drebrin A within somatosensory cortex layer I was smaller for the FAD model mice, when compared to the corresponding region of WT mice (P < 0.0005). However, the areal density of postsynaptic spines containing drebrin A was relatively constant from 3 to 18 months and beyond for both genotypes, suggesting that drebrin A confers stability to postsynaptic spines. Further measurements confirmed that the reduced proportion of drebrin A-containing spines in brains of FAD mice at 6 months is due to the greater size and areal density of spine profiles lacking drebrin A. Thus, soluble Abeta could affect spines lacking drebrin A more strongly than spines containing drebrin A. At 6 months and older, a larger fraction of spinous drebrin A in 2xKI mice was located near the synaptic membrane, as compared to those of WT mice. This pattern may reflect an altered trafficking of synaptic molecules within spines, a factor adding to the decline of synaptic function and plasticity.     

Concordance between qualitative and quantitative cultures in burned patients. Analysis of 2886 cultures

OBJECTIVE: To determine the concordance between superficial cultures (SC) and quantitative cultures (QC) in the diagnosis of wound infection in burn patients. METHOD: Sample: All SC and QC taken from the same patient, site and during the same surgery were analysed. Variables: On the SC, the microorganism (MO) and its amount defined subjectively by the microbiologist was recorded (negative, very low, low, regular and abundant). On the QC, the MO and its amount were expressed as colony forming units per gram of tissue (CFUs/g). Statistics: Kappa index of agreement beyond chance; Wilcoxon and Kruskall-Wallis for continuous variables and chi(2) for categorical variables were used with a p<0.05 indicating statistical significance. RESULTS: One thousand four hundred and forty three pairs of cultures were analyzed. The concordance between SC and QC (Kappa index) was 52%. On the SC, only when the microbiologist subjectively informed "abundant" MOs there was a significant difference (p<0.0001). There were 6.1% of QCs with more than 10(5) CFUs/g and the most frequent MOs isolated were: S. aureus (27.9%), E. coli (11.6%), P. aeruginosa (11.6%), E. faecalis (11.6%) and S. epidermidis (7.0%). CONCLUSIONS: SC has a moderate concordance with the QC showing a low reliability between the two methods. The subjective information given by the microbiology technician in the SC is not precise. A study in which the two methods be compared blindly against the reference standard, in a prospective cohort of patients, it is needed to discriminate which of two methods it is the most accurate one determining sensitivity and specificity.     

Validation of 2001 Partin tables in Turkey: a multicenter study

OBJECTIVE: Although Partin tables were developed in United States to predict the stage of prostate cancer preoperatively, they are used by many clinics throughout the world assuming that these figures apply to their population as well. However the predictive value of current Partin tables, which was updated in 2001, has not been validated in most of the countries as well as in Turkey. Therefore, we evaluated the validity of 2001 Partin tables, for the ability to predict the pathological stage in Turkish patients. PATIENTS AND METHODS: The clinical and pathological findings of 1043 patients who have had radical prostatectomy were assessed. Serum PSA values, clinical stage, biopsy Gleason score and the pathological features of the radical prostatectomy specimens were collected from each clinic and evaluated. The predictive value of Partin nomogram and pathological findings of prostatectomy specimens were compared and analyzed according to Receiver Operating Characteristics (ROC) analysis. RESULTS: Median age of the patients was 60 (45-74). In the presented study, percentage of patients with clinical stage T1c was 43%. Patients with Gleason score of 2-4 in biopsy constituted 23.4% of the study group. In the present study, the ratio of the patients with serum PSA higher than 10 ng/ml was 39.6%. Organ confined disease, seminal vesicle involvement, lymph node metastases ratios were 64.7%, 10.3%, 1.8% respectively. Area Under Curve (AUC) values for organ confined disease, seminal vesicle involvement and lymph node involvement were calculated as 0.665, 0.733 and 0.759 respectively. CONCLUSION: It appears that Partin tables have a reasonable predictive value for the final pathological features like organ confined disease, seminal vesicle and lymph node involvement in Turkish patients. This multicenter study showed that current Partin tables could also be used in Turkish patients with comparable accuracy.     

N- and C-terminal modifications of nociceptin/orphanin FQ generate highly potent NOP receptor ligands

Previous structure-activity studies on nociceptin/orphanin FQ (N/OFQ) identified [Phe(1)Psi(CH(2)NH)Gly(2)]N/OFQ(1-13)-NH(2) and [Nphe(1)]N/OFQ(1-13)-NH(2) as a N/OFQ peptide receptor (NOP) partial agonist and pure antagonist, respectively. The addition of fluorine to the Phe(4) or the insertion of a further pair of basic amino acids Arg(14)-Lys(15) generate potent agonists. On the basis of these findings, we combined in the N/OFQ-NH(2) template the chemical modifications Arg(14)-Lys(15) and (pF)Phe(4) that increase the agonist potency with those conferring partial agonist (Phe(1)Psi(CH(2)NH)Gly(2)) or pure antagonist (Nphe(1)) properties. Twelve peptides were synthesized and pharmacologically evaluated in Chinese hamster ovary cells expressing the human recombinant NOP and in electrically stimulated mouse vas deferens and guinea pig ileum assays. All peptides behaved as NOP ligands; the chemical modifications Arg(14)-Lys(15) and (pF)Phe(4) increased ligand affinity/potency. Peptides with the normal Phe(1)-Gly(2) peptide bond behaved as full agonists, and those with the Phe(1)Psi(CH(2)NH)Gly(2) modification behaved as partial agonists, while those with the Nphe(1) modification behaved as partial agonists or pure antagonists depending on the presence or absence of the (pF)Phe(4) modification, respectively. The full agonist [(pF)Phe(4),Arg(14),Lys(15)]N/OFQ-NH(2), the partial agonist [Phe(1)Psi(CH(2)NH)Gly(2),(pF)Phe(4),Arg(14),Lys(15)]N/OFQ-NH(2), and the pure antagonist [Nphe(1),Arg(14),Lys(15)]N/OFQ-NH(2) represent the most potent peptide ligands for NOP.     

Effect of cyclosporine, mycophenolate mofetil, and their combination with steroids on apoptosis in a human cultured monocytic U937 cell line

Transplant patient plasma produces an increased rate of mononuclear cell apoptosis despite a normal serum creatinine value. Immunosuppressive medications may be one factor that causes an altered apoptotic pattern. We evaluated the in vitro effects of various doses of cyclosporine, mycophenolate mofetil, and steroids on apoptosis of a cultured human monocytic U937 cell line, using estimates by fluorescence microscopy and annexin V assays. Increasing cyclosporine concentrations (100 to 800 ng/mL) progressively increased apoptosis rates (16% to 32%). The combination of steroid (0.01 microg/mL) and cyclosporine increased the apoptosis rate to 45%. Mycophenolate mofetil alone (0.3 microg/mL) led to an apoptosis rate of 34%. Therapeutic levels of mycophenolate mofetil from 3 to 7 microg/mL led to apoptosis rates from 56% to 67%. The combination of cyclosporine, steroid, and mycophenolate mofetil increased the rate of apoptosis to 95%. Immunosuppressive therapy may contribute to the high rate of apoptosis observed among mononuclear cells of transplanted patients. This effect may alter patient susceptibility to infections and contribute to a unique mechanism of immunosuppression.