Search

The pharmacophore properties of a new series of potential purinoreceptor (P2X) inhibitors determined using a coupled neural network and the partial least squares method with iterative variable elimination (IVE-PLS) are presented in a ligand-based comparative study of the molecular surface by comparative molecular surface analysis (CoMSA). Moreover, we focused on the interpretation of noticeable variations in the potential selectiveness of interactions of individual inhibitor-receptors due to their physicochemical properties; therefore, the library of artificial dipeptide receptors (ADP) was designed and examined. The resulting library response to individual inhibitors was arranged in the array, preprocessed and transformed by the principal component analysis (PCA) and PLS procedures. A dominant absolute contribution to PC1 of the Glu attached to heptanoic gating acid and Phe bonded to the linker m -phenylenediamine/triazine scaffold was revealed by the PCA. The IVE-PLS procedure indicated the receptor systems with predominant Pro bonded to the linker and Glu, Gln, Cys and Val directly attached to the gating acid. The proposed comprehensive ligand-based and simplified structure-based methodology allows the in-depth study of the performance of peptide receptors against the tested set of compounds., Competing Interests: The authors declare no conflict of interest.

An artificial polypeptide receptor (APR) library was created by using the self-organization of N-lipidated peptides attached to cellulose via m-aminophenylamino-1,3,5-triazine. The response of the library was probed using a series of novel H3 receptor ligands. Since no guidelines on how to design an APRs selective vs certain receptor types exist, a diverse set of amino acids (Ala, Trp, Pro, Glu, His, Lys and Ser) were used and coupled with one of three gating fatty acids (palmitic, ricinoleic or capric). A competitive adsorption-desorption of an appropriate reporter dye was used for the indirect visualization of the interactions of guests with particular receptors. The resulted library response to individual inhibitors was then arranged in a matrix, preprocessed and analyzed using the principal component analysis (PCA) and partial least squares (PLS) method. The most important conclusion obtained from the PCA analysis is that the library differentiates the probed compounds according to the lipophilicity of the gating unit. The PC3 with a dominant absolute contribution of the receptors containing Glu allowed for the best separation of the ligands with respect to their activity. This conclusion is in agreement with the fact that Glu 206 is a genuine ligand counterpart in the natural histamine receptor.

Urease is a virulence factor found in various pathogenic bacteria. It is essential in colonization of a host organism and in maintenance of bacterial cells in tissues. Due to its enzymatic activity, urease has a toxic effect on human cells. The presence of ureolytic activity is an important marker of a number of bacterial infections. Urease is also an immunogenic protein and is recognized by antibodies present in human sera. The presence of such antibodies is connected with progress of several long-lasting diseases, like rheumatoid arthritis, atherosclerosis or urinary tract infections. In bacterial ureases, motives with a sequence and/or structure similar to human proteins may occur. This phenomenon, known as molecular mimicry, leads to the appearance of autoantibodies, which take part in host molecules destruction. Detection of antibodies- binding motives (epitopes) in bacterial proteins is a complex process. However, organic chemistry tools, such as synthetic peptide libraries, are helpful in both, epitope mapping as well as in serologic investigations. In this review, we present a synthetic report on a molecular organization of bacterial ureases - genetic as well as structural. We characterize methods used in detecting urease and ureolytic activity, including techniques applied in disease diagnostic processes and in chemical synthesis of urease epitopes. The review also provides a summary of knowledge about a toxic effect of bacterial ureases on human body and about occurrence of anti-urease antibodies in long-lasting diseases.

Introduction: Cancer of thyroid gland is the most common malignancy of the endocrine system. The treatment improvement could be achieved by early diagnosis. The aim of the study was to identify cancer specific antigenes with use of peptide libraries., Material and Methods: The material from 6 patients with thyroid cancer (4 with papillary cancer, 1 with follicular cancer and 1 with oxyphilic tumor) were analyzed. It was performed with use of lipophylic peptide libraries by direct comparison of staining of specimens prepared from normal and malignant tissue., Results: Preliminary results confirm practical value of peptide libraries in early diagnostics of thyroid cancer., Conclusions: It is important to optimize construction of peptide libraries by using different staining agents hydrolyzed by proteases.

New therapies for vancomycin-resistant Enterococcus faecium (VREF) infections are urgently needed. We describe the treatment of 15 patients with VREF infection with quinupristin/dalfopristin (RP 59500), a new injectable streptogramin antibiotic. Primary infections treated were bacteremia (4), urinary tract (4), intraabdominal (5), otitis externa (1), and meningitis (1). Minimum inhibitory concentrations for quinupristin/dalfopristin ranged from 0.5 microgram/ml or less to 2 micrograms/ml, and minimum bactericidal concentrations were greater than 64 micrograms/ml for all VREF isolates tested. Peak serum inhibitory titers following infusion of quinupristin/dalfopristin ranged from 1:8 to 1:64; all bactericidal titers were less than 1:2. Development of resistance to quinupristin/dalfopristin during therapy was not observed. The only drug-related adverse effect noted was phlebitis in 4 patients; all had received quinupristin/dalfopristin by peripheral venous infusion. Three patients had clinical and bacteriologic cures. Relapses occurred in 5 patients with recovery of VREF from infected sites in post-treatment cultures. Ten patients died of severe underlying disease; VREF was believed to contribute directly to the death of only 1 patient. While evaluation of clinical efficacy was complicated by the severity of underlying disease in patients with VREF infection, our experience suggests that quinupristin/dalfopristin is a safe and potentially useful agent for the treatment of VREF infections.

The first documented case of algal meningitis due to Prototheca wickerhamii is reported in a patient with AIDS. The initial CSF culture yielded only Cryptococcus neoformans. P. wickerhamii was isolated on four subsequent lumbar punctures. The patient died, and at autopsy the alga was isolated from leptomeninges over the brain and about the spinal cord. Histologic sections from numerous locations of the brain revealed masses of cryptococci and prototheca.

New third generation cephalosporins have been recommended as single agent antibiotic therapy in the treatment of postoperative infections. This study compares the new third generation cephalosporin ceftizoxime with cefoxitin, clindamycin and gentamicin in the treatment of postcesarean section endomyometritis. The results indicate that the clindamycin and gentamicin regimen is more efficacious in the treatment of severe infection after cesarean section than either ceftizoxime or cefoxitin regimens. Therefore, the results of this study suggest caution in substituting single drug antibiotic therapy with cefoxitin or the third generation cephalosporins for the standard clindamycin and gentamicin regimen in the treatment of postcesarean section endomyometritis until more clinical data are available.

Data processing using nonparametric statistics was performed using a 'direct linear plot' algorithm of ECB. ECB (Eisenthal and Cornish-Bowden) is a computer program designed to calculate the Km and V parameters in enzyme kinetics. It is also suitable for estimation of EC50 (ligand or drug concentration for 50% effect) in pharmacological studies.

Onchocerciasis was diagnosed when a skin biopsy specimen immersed in saline revealed microfiliariae. The patient was a 22-year-old student from Cameroon, West Africa, complaining of small, recurrent, pruritic papules on his thighs. Chemotherapy with ivermectin, an established antiparasitic agent with newly recognized anti-onchocercal potential, was well tolerated, and microfilariae were not detected in post-therapy skin biopsy specimens. The diagnosis of onchocerciasis should be entertained in individuals returning or emigrating from endemic areas.

A long term follow up (mean 7.2 years) of 30 children with anorexia nervosa (mean age at onset 11.7 years) was carried out. The outcome was good in only 18 (60%), 10 children remaining moderately to severely impaired and two died. Poor prognostic factors included early age at onset (less than 11 years), depression during the illness, disturbed family life and one parent families, and those in which one or both parents had been married before.

The efficacy of a single antibiotic--Timentin (ticarcillin with clavulanic acid)--was compared with a standard two antibiotic regimen (clindamycin and gentamicin) for the treatment of endomyometritis after cesarean delivery. The regimens were 3 grams of ticarcillin plus 100 milligrams of clavulanic acid given intravenously every four hours, or 600 milligrams of clindamycin given intravenously every six hours plus 3 to 5 milligrams per kilogram per day of gentamicin given intramuscularly. The diagnosis of endomyometritis was based upon an oral temperature of 100.4 degrees F. or higher on any two occasions, excluding the first 24 hours post partum, uterine tenderness and the absence of another focus of infection. Ninety-one patients were treated. Treatment failure rates were three of 49 in the clindamycin and gentamicin group and four of 42 of the ticarcillin plus clavulanic acid group. Treatment failures did not appear to be different from successes demographically or in risk factors for endomyometritis. The results of this study suggest that ticarcillin with clavulanic acid is as effective in the treatment of postcesarean endomyometritis as the standard regimen of clindamycin and gentamicin.

A prospective, randomized study of intravenous followed by oral ciprofloxacin compared with the combination of intravenous clindamycin and gentamicin was conducted in 122 women hospitalized with pelvic infections. Clinical diagnoses included endometritis (97 patients) and uncomplicated pelvic inflammatory disease (25 patients). Treatment successes for endometritis included 42 of 50 (84 percent) patients treated with ciprofloxacin compared with 35 of 47 (75 percent) treated with the clindamycin-gentamicin combination. Treatment successes for acute salpingitis included 10 of 10 (100 percent) treated with ciprofloxacin and 13 of 15 (87 percent) treated with clindamycin-gentamicin. Ciprofloxacin successfully eradicated Chlamydia trachomatis in 11 of 12 patients as did clindamycin-gentamicin in six of seven patients. In this study of pelvic infection, ciprofloxacin demonstrated efficacy comparable with the combination of clindamycin and gentamicin, and is effective against C. trachomatis.

Septicemia due to Pseudomonas putrefaciens was found in an elderly man with chronic leg ulcers. This organism is rarely cultured from human material and has been reported to cause skin and ear infections in only a few patients. Its potential for invasiveness is documented in this case for the fourth time.

Five cases of extra-intestinal Campylobacter fetus infections are described and an additional 242 cases are reviewed from the literature. A variety of clinical syndromes are encountered including endocarditis; thrombophlebitis; meningitis; pneumonia and pleuritis; and infectious arthritis. Thirty-eight per cent of patients presented with bacteremia enteritis. Campylobacter fetus demonstrates a preference for endovascular surfaces. The majority of patients are male and have an underlying illness. Mortality is increased in patients infected with C. fetus intestinalis. Therapy is based on in vitro antibiotic susceptibility tests although the organism is usually sensitive to an aminoglycoside and chloramphenicol.

A 48-year-old Puerto Rican woman developed extensive ulcers on her buttocks, right arm, and thighs over a 3 1/2-year period. The lesions began as small, subcutaneous nodules which subsequently ulcerated and expanded up to 19 cm in diameter. Biopsy of both ulcerated and nonulcerated lesions showed acid-fast bacilli. Culture of both types of lesions grew Vibrio extorquens, a partially acid-fast methanolophilic organism not previously associated with disease in humans. The patient developed agglutinating antibody, titer 1:80, to this organism. The disease responded to treatment with antibiotics to which the organism was sensitive in vitro.

Two patients hyperinfected with Strongyloides stercoralis (an intestinal nematode) are described. Both were both in Puerto Rico and had left the island six to 15 years previously; both were receiving adrenal steroids (one for Hodgkin's disease and the other for Goodpasture's syndrome). One died shortly after diagnosis, but the other survived the hyperinfection syndrome and complicating bacterial sepsis and meningitis. In addition to our case reports, 103 previously described cases of presumed strongyloides hyperinfection are reviewed. Among 89 patients immunocompromised by therapy or disease, the mortality rate was 86%; bacterial sepsis often contributed to the fatal outcome. In most cases, infection was acquired in an endemic area, sometimes long before the hyperinfection syndrome occurred. The few patients who had never been to an endemic area had a history of prolonged contact with highly soiled material, an observation suggesting cross infection from a contaminated person. When administered in time, thiabendazole, the drug of choice for strongyloidiasis, was effective in 70% of cases. If intestinal infection with S. stercoralis is detected and treated before immunosuppressive therapy is initiated and if a high index of suspicion for the hyperinfection syndrome is maintained while immunosuppressive therapy is given, the mortality from this disease should decrease.

Patients who had contaminated traumatic perforations of the gastrointestinal tract and those with acute peritonitis resulting from acute surgical inflammatory conditions were treated with piperacillin or cefoxitin infused intravenously as single therapy for a minimum of five days. Thirty-four patients were given 4.5 grams of piperacillin every six hours and 26 patients, 2.0 grams of cefoxitin every six hours. In the piperacillin group, 63 organisms (34 aerobes and 29 anaerobes) were isolated from pretreatment cultures, while in the cefoxitin group, 73 organisms (35 aerobes and 38 anaerobes) were isolated. Clinical recovery was achieved in 31 of 34 patients receiving piperacillin therapy and in 24 of 26 patients receiving cefoxitin therapy. Organisms were found to be resistant to the respective drug in two piperacillin-treated patients and in one cefoxitin-treated patient, and the patients were given other antibacterial treatment. One patient from each treatment group died of causes unrelated to septic conditions. No serious adverse effects occurred from either antibiotic.

The enzyme xanthine: acceptor oxidoreductase found in rat heart equilibrates between three forms differing in electron acceptor specificity. Form D transfers electrons exclusively to NAD+ and accounts for 85% of total oxidoreductase activity. Form O transfers electrons to molecular oxygen and accounts for 8%. The D/O form prefers NAD+, but without NAD+ transfers electrons to oxygen. Interconversion from D to O and O to D forms is catalyzed by sulfhydryl group-modifying reagents: Cd2+, Cu2+, disulfiram, and heating with dithiothreitol. This suggests that sulfhydryl groups participate in the first stage of enzyme conversion. The NADH/NAD+ concentration ratio may regulate the dehydrogenase activity of xanthine:acceptor oxidoreductase (NAD+-dependent activity of D and D/O forms). Accumulating NADH inhibits hypoxanthine hydroxylation. The amount of form O increases during cardiac ischemia, facilitating superoxide radical-ion generation. Also, NADH/NAD+ does not regulate form O, promoting adenylate nucleotide pool depletion, especially in the heart which has low de novo purine nucleotide synthesis.

A case of asthma in an adolescent male is presented. Involvement of the patient in individual, group and family psychotherapy is discussed in detail and particular emphasis placed on the use of family sessions as a therapeutic tool. Alexander's concept of the "repressed cry for the lost mother" is suggested as of aetiological importance.

A new single-antibiotic combination of ticarcillin and clavulanic acid was compared with the standard two-drug regimen of clindamycin and gentamicin in the treatment of post-cesarean endomyometritis. The regimens were as follows: 3 g of ticarcillin plus 100 mg of clavulanic acid intravenously every four hours; or 600 mg of clindamycin intravenously every six hours plus 3 to 5 mg/kg per day of gentamicin intramuscularly. The prospective randomized schedule was calculated such that half the patients were assigned to each treatment group. The diagnosis of endomyometritis was based upon an elevated oral temperature of 100.4 degrees F or higher on any two occasions, excluding the first 24 hours after delivery, uterine tenderness, and the absence of other foci of infection. Lochial discharge was foul in most cases. Forty-seven patients were treated. Treatment was successful in all patients who received clindamycin and gentamicin; ticarcillin plus clavulanic acid failed in two of 23 (9 percent) patients. Patients in whom treatment failed did not appear to be different from those in whom treatment was successful on demographic variables or in terms of risk factors for endomyometritis. The difference between the treatment failure rates was not statistically significant. This study suggests that the single-drug combination of ticarcillin plus clavulanic acid is effective in the treatment of post-cesarean endomyometritis when compared with the standard regimen of clindamycin and gentamicin.

By means of the new medium, nonspecific urethritis (NSU) chocolate agar, NSU corymebacteria were isolated from patients with asymptomatic bacteriuria, bacteremia, cervicitis, conjuctivitis, and pericarditis, and also with bone marrow, wound, and cul-de-sac infections. The NSU corynebacteria were considered the etiologic agents. On the basis of biochemical reactions, antibiotic sensitivity, and complement fixation tests some isolates were the same microorganisms. Both patients with conjunctivitis were infected with the same NSU corynebacteria. A second isolate was cultured from patients with osteomyelitis and cervicitis, while a third was recovered from an infected leg wound and from a patient with pericarditis. Seven of the isolates, when injected into rabbits hypersensitive to four NSU corynebacteria isolated from the inflamed epididymis of patients with epididymitis, elicited delayed hypersensitivity reactions, which indicated that they also were related antigenically. It is suggested that nonspecific urethritis and eididymitis may represent an infection with NSU corynebacteria, or may be an extension of bacteriuria due to these microorganisms, with a delayed hypersensitivity reaction as a possible additional complication. Colony counts on NSU chocolate agar of the bacteria in urines from male and female patients were higher than those obtained on conventional agar media. NSU chocolate agar is superior to other agar media for the isolation of pathogenic and saprophytic bacteria not only from the urogenital tract but also from other foci of infection. It is easily prepared from commercial blood agar plates and its use should be considered when a selective medium is not required.