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Biomedical subjects

R Aly

Publications and source records attributed to R Aly.

At least 37 records · Page 2Linked to original sources
PubMed1997

A multicenter, placebo-controlled, double-blind study of intermittent therapy with itraconazole for the treatment of onychomycosis of the fingernail.

BACKGROUND: Onychomycosis is the most frequent cause of nail disease and represents 30% of all mycotic infections of the skin. OBJECTIVE: Our purpose was to compare the effectiveness and tolerability of intermittent dosing of itraconazole ("pulse therapy") with placebo in fingernail onychomycosis. METHODS: Seventy-three patients with clinically and mycologically diagnosed fingernail onychomycosis were randomly selected to receive itraconazole, 200 mg twice daily, or placebo for the first week of each month for 2 consecutive months; patients were observed for 19 weeks. Seventy-one patients received the study medication and were included in the safety analysis. Efficacy of treatment was evaluated in 46 patients. RESULTS: A significantly greater proportion of itraconazole-treated patients than placebo-treated patients achieved clinical success (77% vs 0%), mycologic success (73% vs 13%), and overall success (68% vs 0%). No itraconazole-treated patient had a clinical or mycologic relapse during the follow-up period. Ten itraconazole-treated patients (28%) and nine placebo-treated patients (26%) had adverse events. Three patients discontinued treatment for safety reasons. CONCLUSION: Pulse therapy with itraconazole for 2 consecutive months produces significantly greater clinical, mycologic, and overall success than placebo. Short-term itraconazole pulse therapy for fingernail onychomycosis is effective and well tolerated.

Adult↗
PubMed1997

Double-blind, randomized comparison of itraconazole capsules vs. placebo in the treatment of toenail onychomycosis.

Three multicenter, randomized, double-blind, placebo-controlled studies were conducted to determine whether twelve weeks of therapy with itraconazole, 200 mg, was effective in the treatment of dermatophyte infection of the toenail. Significantly more patients treated with itraconazole (110 patients) than with placebo (104 patients) achieved clinical (65 percent vs. 3 percent) and mycologic (54 percent vs. 6 percent) success. The mean percentage of affected reference nail before the initiation of therapy was 76 percent. Adverse events were comparable in the two treatment groups. These findings demonstrate that twelve weeks of continuous itraconazole, 200 mg once daily, is a highly effective, well-tolerated therapy for the management of toenail onychomycosis.

Adolescent↗
PubMed1996

Cloning from Leishmania major of a developmentally regulated gene, c-lpk2, for the catalytic subunit of the cAMP-dependent protein kinase.

Protein kinases are important in the regulation of cellular processes including growth and differentiation. Using the polymerase chain reaction with oligonucleotide primers derived from conserved regions of cAMP-dependent protein kinases (PKAs), three different DNA fragments were amplified from leishmanial genomic DNA. One fragment was used to isolate a stage specific gene, c-lpk2, from a Leishmania major genomic library. This gene shows high homology to other eukaryotic PKAs, and the open reading frame encodes a 332 amino acid protein with a predicted molecular mass of 38.2 kDa. When aligned with other PKAs the leishmanial enzyme has a unique eight amino acid extension at the carboxy terminus. The c-lpk2 gene is present as a single copy in L. major, L. donovani and L. amazonensis. The 5'-flanking region contains a polypyrimidine rich tract upstream from the predicted ATG start codon. The gene is highly expressed in promastigotes and barely detectable in amastigotes of L. major. Temperature increase was shown to rapidly down-regulate c-lpk2 expression. Transfer of L. amazonensis promastigotes to 35 degrees C resulted in the rapid disappearance of c-lpk2 mRNA (> 70% in 1 h), while at 26 degrees C the mRNA was more stable. The strict temperature dependence of mRNA degradation rate suggests that PKA expression is regulated post-transcriptionally.

Amino Acid Sequence↗
PubMed1996

Common superficial fungal infections in patients with AIDS.

Superficial mycotic infections such as seborrheic dermatitis, tinea pedis, tinea corporis, and onychomycosis are common in patients infected with human immunodeficiency virus (HIV). In communities where HIV infections are frequent, some of these clinical presentations serve as markers of the stage of HIV infection. The diagnosis of superficial fungal infection in HIV-positive patients may be difficult because of atypical clinical manifestations. Therefore, to ensure a correct diagnosis, skin scrapings should be collected for potassium hydroxide preparations and cultures. Most forms of dermatophytosis in HIV-positive patients respond well to many topical antifungal agents, such as azoles, terbinafine, and ciclopirox olamine. If the disease is chronic and extensive, then ketoconazole, fluconazole, and itraconazole are each effective.

AIDS-Related Opportunistic Infections↗
PubMed1995

Topical sphingolipids in antisepsis and antifungal therapy.

Sphingosine and sphinganine, free sphingolipids of the stratum corneum, are, in vitro, strongly inhibitory for both bacteria and fungi. Whether or not they are suitable, indeed active, in vivo was examined: (i) on human volunteers, first as a preventative antiseptic against subsequently applied Staphylococcus aureus and Candida albicans, and second as a restorative antiseptic against the previously expanded normal skin flora; and (ii) on guinea-pigs as therapy for experimental C. albicans and Trichophyton mentagrophytes infections. In the antiseptic studies, which involved 200 micrograms/cm2 of sphinganine in ethanol (50 microliters of a 1.6% solution), up to three-log reductions in the population of target micro-organisms were obtained, compared with vehicle and untreated controls (P < 0.001). The daily application of sphingosine as 1.5% ethanol-petrolatum ointment was able to diminish inflammation slightly in dermatophyte-infected guinea-pigs (P = 0.02-0.05), although the animals remained culture positive over the 3-week sampling period. The candida infections, treated daily with 1.5% sphinganine in ethanol, showed no improvement in inflammation compared with controls, except for 2 days of the 2-week observation period (P = 0.01-0.03); however, by the fourth day of therapy the yeast was eliminated in 75% of animals. No gross toxicity was observed among animals or human volunteers. These experiments further support simple sphingolipids as important antimicrobial agents of the cutaneous barrier and point toward a new biochemical approach in treating infectious disease.

Animals↗
PubMed1994

A regulatory role for the 5' and 3' untranslated regions in differential expression of hsp83 in Leishmania.

Exposure of Leishmania promastigotes to temperatures typical of mammals result in a stress response, which is accompanied by an increase in the steady state level of heat shock transcripts and their translation. Accumulation of the heat shock protein (hsp83) mRNA occurs due to differential decay rates at the altered temperatures, while transcription is unaffected. A similar pattern of post-transcriptional regulation was observed for a transfected chloramphenicol acetyltransferase (CAT) gene, which was flanked at both ends by intergenic regions (IR) of hsp83. Shortening the 5' untranslated region (UTR) by 100 nts produced an active CAT enzyme, but abolished the temperature-dependent regulation of the CAT-hsp83 mRNA turn-over. The 3' UTR is also involved in the temperature-dependent degradation of hsp83 mRNA, since exchange of the hsp83 3' UTR with a parallel fragment from a non-heat shock gene abolished the differential turn-over of CAT mRNA. Thus, the regulated decay of hsp83 mRNA is controlled by sequence or conformational elements present in both upstream and downstream UTRs. Like the endogenous hsp83, translation of CAT mRNA which contained hsp83 UTRs was higher at 35 degrees C. This was observed only with transcripts in which stability increased at elevated temperatures. Modifications which abolished the temperature dependence of CAT mRNA decay, eliminated its elevated translation at the higher temperatures. The correlation suggests a mechanistic link between the translational machinery and mRNA stability.

Animals↗
PubMed1994

Functional analysis of cis-acting DNA elements required for expression of the SL RNA gene in the parasitic protozoan Leishmania amazonensis.

DNA sequences, that control expression of the spliced leader (SL) RNA gene in the parasitic protozoan Leishmania amazonensis, were mapped by block substitution mutagenesis. In the absence of a functional in vitro system for transcription, no promoter elements have yet been identified in this organism. We therefore developed an alternative in vivo approach, in which the SL RNA gene was tagged and then subjected to a series of linker scanning mutations. Each tagged and mutated SL RNA construct was introduced into parasite cells via the pX transfection vector, and was examined for expression of the tagged SL RNA followed by characterization of its transcriptional start site. The replacement of a critical DNA element was expected to prevent expression of the tagged SL RNA. We found that the putative SL RNA promoter is complex and includes two elements: one is located upstream to the coding region, between positions -30 to -70; and the other is located between -10 to +10, and includes transcribed sequences. In addition to the functional relationship between the SL RNA and vertebrate U snRNAs, we found structural similarities in their regulatory elements, which may possibly indicate a common evolutionary ancestry for these molecules.

Animals↗
PubMed1994

Expression of heat shock protein 83 in Leishmania is regulated post-transcriptionally.

Mechanisms for regulation of heat shock protein (hsp) 83 expression were examined in Leishmania amazonesis. Transcripts of hsp83 accumulated upon temperature elevation; however, in contrast to non-protozoan eukaryotes (i.e. Drosophila, yeast, avian or human cells), no transcriptional activation was observed. The increase in the hsp83 mRNA level evolved from temperature induced variations in mRNA turn-over: the hsp83 transcript was rapidly degraded at normal temperatures, whereas heat shock led to its stabilization. The quick decay of the mRNA at lower temperatures was dependent on active protein synthesis. A similar pattern of regulation was observed for the transfected chloramphenicol acetyltransferase (CAT) gene, which was flanked by sequences from the hsp83 intergenic region (IR), and cloned into the pX transfection vector (pX-ICI). CAT mRNA was abundant at normal temperatures and further accumulated upon temperature elevation. The altered turn-over rates of CAT mRNA at the different temperatures were observed only in the presence of flanking hsp83 IR sequences. The increase in temperature also affected translational regulation of hsps, and synthesis of hsp83 was more efficient at 35 degrees C than at 26 degrees C. However, the effect of translation was transient, and the steady state level of the protein was hardly altered.

Animals↗
PubMed1994

Ecology and epidemiology of dermatophyte infections.

Our knowledge of ecology and epidemiology of dermatophytes and the factors influencing their transmission has helped us understand better the natural history of dermatophytoses. It seems that the anthropophilic agents of scalp infection are being eradicated in developing nations. The exception is Trichophyton tonsurans-related tinea capitis in North America. Microsporum canis is a prevalent agent of tinea capitis in many regions of the world, and this could be related to close association of humans with their pets. Trichophyton violaceum is endemic in certain parts of Eastern Europe, Africa, Asia, and South America but not in North America. Trichophyton rubrum is the most common cause worldwide of tinea pedis, nail infection, tinea cruris, and tinea corporis. Although the incidence of tinea capitis is declining in developed nations, tinea pedis and onychomycosis are becoming more common. The increased use of athletic shoes both by men and women and communal bathing could be contributing factors. Five or six species account for most dermatophytoses globally.

Animals↗
PubMed1994

Topical griseofulvin in the treatment of dermatophytoses.

Whether griseofulvin, which pioneered oral antifungal therapy, works topically has long been an open question. The effectiveness of a 1% griseofulvin spray formulation and the vehicle alone against experimentally induced Trichophyton mentagrophytes lesions on the forearms of 16 healthy volunteers and in the treatment of 100 tinea pedis patients (various dermatophytes) was evaluated in a double-blind study. After treatment of the 58 induced lesions twice daily for 14 days with topical griseofulvin (28) or placebo (30), 89% of lesions receiving griseofulvin were mycologically negative compared with 30% in the placebo group (P < 0.0001). In the tinea pedis patients who applied medication once daily for 4 weeks the mycological cure was 79.2% on the fourth week and 80.9% 2 weeks post-treatment. Resurgence of dermatophytes quickly followed the end of treatment in the placebo group only, which had a mycological cure rate of 34% (week 6). Administration of a topical formulation of griseofulvin thus may be an effective treatment for interdigital dermatophyte infections.

Administration, Topical↗
PubMed1993

Intergenic sequences from the heat-shock protein 83-encoding gene cluster in Leishmania mexicana amazonensis promote and regulate reporter gene expression in transfected parasites.

Regulation of expression from hsp83 gene cluster encoding heat-shock protein (HSP) 83 of the protozoan parasite Leishmania mexicana amazonensis (L.m.a) was examined. The first gene from this cluster, along with 8 kb of flanking sequences, was cloned, and intergenic region (IR) sequences were found upstream from the cluster. L.m.a. parasites were electroporated with a plasmid (pICI) in which the chloramphenicol acetyltransferase (CAT)-encoding gene (cat) was cloned between two IRs derived from an internal repeat unit of the hsp83 cluster, resulting in CAT activity at 26 degrees C. Exposure of cells transfected with this plasmid to a 35 degrees C heat shock led to an increase in CAT activity, within a range similar to that observed for the accumulation of hsp83 steady-state mRNA at 35 degrees C. S1 analysis of the hsp83 mRNA showed that the major part of the IR was transcribed and mostly present as 3' non-translated extensions. Deletion analysis of the flanking regions indicated that the presence of IR sequences, both upstream and downstream from cat, was critical to its expression. Partial deletions that removed the original AG splice acceptor site (leaving 289 bp upstream) and downstream IR sequences (leaving 200 bp) did not eliminate CAT activity. However, this combined deletion altered the effect of temperature on cat expression in transfected cells, as compared with the activity measured in cells transfected with the original plasmid.

Amino Acid Sequence↗
PubMed1993

Elimination of Staphylococcus aureus nasal carriage in health care workers: analysis of six clinical trials with calcium mupirocin ointment. The Mupirocin Collaborative Study Group.

Six double-blind, independently randomized studies evaluated the efficacy and safety of calcium mupirocin ointment in eliminating nasal carriage of Staphylococcus aureus among health care workers. Healthy volunteers with stable nasal carriage of S. aureus (n = 339) received either calcium mupirocin ointment (n = 170) or an identical placebo ointment (n = 169) intranasally for 5 days. Nasal carriage was eliminated 48-96 hours after completion of treatment in 130 (91%) of 143 evaluable volunteers receiving mupirocin but in only 8 (6%) of 142 evaluable volunteers receiving placebo. The 85% crude difference represents a 90% pooled (adjusted) estimate of the risk difference (95% confidence interval, 0.86-0.95) and a risk ratio of 16 (P < .0001). This effect of treatment with mupirocin was observed consistently (risk ratio, 8-32) in all six centers. In addition, 96 of the 130 mupirocin-treated volunteers and 1 of the 8 placebo-treated volunteers who were culture-negative at the end of therapy remained free of S. aureus 4 weeks after treatment. Adverse events in each treatment arm were mild and equally frequent. These data, consistent across six institutions, demonstrate that calcium mupirocin ointment administered intranasally for 5 days is safe and effective in eliminating stable nasal carriage of S. aureus.

Administration, Intranasal↗
PubMed1993

Sphingosines: antimicrobial barriers of the skin.

Among the factors that control the survival of microorganisms on human stratum corneum are skin lipids, including sphingosines. Because the antibacterial spectrum of sphinganine resembles that of cell wall antibiotics, electron microscopy of sphinganine-treated and untreated S. aureus was performed; the lipid induced multiple lesions of cell wall, membrane evaginations and loss of ribosomes. However, comparisons of minimal inhibitory concentration of sphinganine for coccal forms and L-forms of S. aureus, which lack cell walls, and of the respective dose-related reductions in colony-forming units demonstrated both the susceptibility of L-forms and their superior resistance. Therefore, cell wall lesions are sequelae of a probable membrane reaction. Candida albicans was susceptible to sphinganine, sphingosine, dimethylsphingosine, and to a lesser degree, stearylamine. Liquid assays of these lipids against Trichophyton mentagrophytes, T. tonsurans and Epidermatophyton floccosum established their high susceptibility to sphingosine and stearylamine. Sphinganine was the least effective, perhaps due to the presence of L isomers; T. tonsurans was the most sensitive. These four lipids were found to be fungistatic, preventing germination and retarding thalli. Antifungal efficacy was confirmed in vitro on stratum corneum.

Adult↗
PubMed1993

Tinea pedis.

Tinea pedis is a term used to encompass several clinically distinctive infections of the skin of the foot. Dermatophytic fungi are primarily responsible for these infections. Several nondermatophytes have been implicated in some patients, particularly for nail infections. The major clinical variants are (1) interdigital infections in which dermatophytes initiate the process by damaging the stratum corneum while the subsequent maceration and leukokeratosis results from overgrowth of bacteria such as Micrococcus sedantarius, Brevibacterium epidermidis, Corynebacterium minutissimum and gram-negative organisms; (2) plantar mocasin type of hyperkeratosis due to T rubrum and found primarily in those with an atopic background; (3) vesiculo-bullous infections in the arch and side of the foot due to an immune response of delayed hypersensitivity to T mentagrophytes.

Antifungal Agents↗
PubMed1992

Antimicrobial activity of sphingosines.

The antimicrobial activity of stratum corneum lipids was examined by screening in vitro various representative phospholipids and sphingolipids. Of mixed galacto-cerebrosides; phosphatidic acid; phosphatidic acid-monomethylester-dioleoyl; phosphatidylethanolamine; phosphatidylethanolamine-beta-oleoyl-gamma-palmitoyl; phosphatidylcholine; D-sphingosine; D,L-sphinganine; 4-D-hydroxysphinganine; oleoyl-sphingosine; N,N-dimethylsphingosine; and stearylamine, only the sphingosines and, to a lesser extent, stearylamine were clearly and profoundly effective against Staphylococcus aureus (4-log reduction at 6.25 micrograms/ml [20 microM]; 2-log reduction at 0.78 mu/ml [2.5 microM]). The sphingosines were similarly active against Streptococcus pyogenes, Micrococcus luteus, Propionibacterium acnes, Brevibacterium epidermidis, and Candida albicans, moderately active against Pseudomonas aeruginosa, and ineffective against Escherichia coli and Serratia marcescens. Both erythro- and threo-isomers were effective. Optimal inhibition was at 60 min incubation at 37 degrees C and at pH 6.5. Antimicrobial activity, which was Ca++ dependent, was confirmed in vivo by topical application and microbial challenge. Because free sphingosines are available in the stratum corneum and other epidermal layers, these lipids may contribute to the cutaneous antimicrobial barrier.

Bacteria↗