Synthesis, antiproliferative, and antiviral activity of certain 4-substituted and 4,5-disubstituted 7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3-d]pyrimidines

The sodium salts of 4-chloro- and several 4-chloro-5-substituted-7H-pyrrolo[2,3-d]pyrimidines were treated with [1,3-bis(benzyloxy)-2-propoxy]methyl chloride (6) to provide the corresponding 4-chloro- and 4-chloro-5-substituted-7-[[1,3-bis(benzyloxy)-2-propoxy]methyl]pyrrolo [2,3-d]pyrimidines (7-11). Debenzylation with boron trichloride at -78 degrees C furnished 4-chloro- and several 4-chloro-5-substituted-7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3- d]pyrimidines (12.16). Subsequent amination of 12-16 yielded the 4-amino-5-substituted-7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3- d]pyrimidines (17-21). Treatment of 14 with methylamine and 13 and 14 with ethylamine yielded the 4-(alkylamino)-5-halo-7-[(1,3-dihydroxy-2- propoxy)methyl]pyrrolo[2,3-d]pyrimidines (22-24). Treatment of 12-15 with hydroxylamine in refluxing 2-propanol yielded the 5-substituted-4-(hydroxyamino)-7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrol o [2,3-d]pyrimidines (25-28). Treatment of compound 12 with Pd/C under a hydrogen atmosphere has furnished the nebularine analogue 31. The antiproliferative activity of compounds 17-28 and 31 was studied using L1210 cells in vitro. The 4-amino- and 4-(hydroxyamino)-5-halogenated derivatives (compounds 18-20, 26-28) inhibited cell growth. Although the effect of compounds 18-20 and 27 on final growth rate was pronounced (IC50 = 2.3, 0.7, 2.8, and 3.7 microM, respectively), cells underwent at least one doubling before cell division stopped. The remaining compounds were less cytotoxic, with IC50's greater than 30 microM for 21, 23, 26, and 28, whereas no inhibition of L1210 cell growth was observed with compounds 17, 22, 24, 25, and 31 at 100 microM. The antiviral activity of these compounds also was tested. Compounds 18-20 and 26-28 were active against human cytomegalovirus and herpes simplex type 1. The 4-amino derivatives (18-20) were more active than the 4-hydroxyamino derivatives (26-28), the 4-amino-5-bromo and 4-amino-5-iodo derivatives produced more than five log reductions in virus titer at concentrations of 10-100 microM. Although some cytotoxicity was observed at these concentrations, compound 19 was active against murine cytomegalovirus in vivo. At 5.6 mg/kg, 14/15 animals survived compared to 10/15 treated with 5.6 mg/kg of ganciclovir or 1/15 treated with placebo.     

The diaphragmatic echo complex: an in vitro study

The brightly echogenic appearance of the diaphragm on routine clinical scans is not easily reconciled with the well-documented echo-poor appearance of muscle elsewhere in the body. A series of specimens of normal human diaphragm freshly excised at autopsy were suspended in a water bath. Articulated arm scans were done varying the angle of the incident beam to the specimen by 5-degree increments and recording the maximum attenuation which allowed visualization (ie, an extinction point). This was accomplished for intact diaphragm, peritoneal membrane alone, and diaphragmatic muscle alone with both membranes stripped. The bright specular echoes seen are due almost exclusively to the membranes (parietal pleura and peritoneum) and the diaphragmatic muscle itself produces only low-level scattered echoes as elsewhere. However, these scattered echoes account for persistent visualization of the diaphragm at steep angles of the incident beam. A considerable portion of the in vivo thickness of the diaphragmatic echo complex is, therefore, produced by diaphragm-lung interface.     

Synthesis and antiviral activity of certain 4- and 4,5-disubstituted 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidines

In vitro evaluation of a series of previously prepared tubercidin analogues revealed that certain 5-halogen-substituted analogues were active against human cytomegalovirus (HCMV) at concentrations lower than those that produced comparable cytotoxicity in uninfected cells. In contrast, tubercidin was cytotoxic at all antiviral concentrations. Even though the antiviral selectivity of the 5-substituted compounds was slight, this observation led us to prepare a series of acyclic analogues. Treatment of the sodium salt of 4-chloropyrrolo[2,3-d]pyrimidine (2) with (2-acetoxyethoxy)methyl bromide (2a) provided the acyclic nucleoside 4-chloro-7-[(2-acetoxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine (3). A nucleophilic displacement of the 4-chloro group with methoxide, methylamine, and dimethylamine yielded the corresponding 4-substituted compounds 4, 5, and 6, respectively, in good yield. Electrophilic substitution (chlorination, bromination, and iodination) was effected at the C-5 position of compound 3 with N-chlorosuccinimide, N-bromosuccinimide, and iodine monochloride, respectively, in methylene chloride. Removal of the acetyl group from these intermediates (7a-9a) with methanolic ammonia at room temperature afforded the 5-chloro (7b), 5-bromo (8b), and 5-iodo (9b) derivatives of 4-chloro-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine. Treatment of compounds 7b-9b with methanolic ammonia at an elevated temperature produced the corresponding 5-halotubercidin analogues 10, 11, and 12, respectively. An alternate procedure for the preparation of these 4,5-disubstituted 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidines involved an electrophilic substitution prior to the condensation of the heterocycle with 2a. Treatment of 2 with N-chlorosuccinimide and N-bromosuccinimide gave compounds 13a and 13b, respectively. The condensation of 13a and 13b with 2a and subsequent treatment with methylamine and ethylamine furnished the corresponding 5-halo-4-substituted-pyrrolo[2,3-d]pyrimidines 14a, 14b, 14c, and 14d, respectively. Evaluation of the target compounds (4-6, 7b-9b, 10-12, and 14a-14d) for cytotoxicity and activity against HCMV and herpes simplex virus type 1 (HSV-1) revealed that all compounds except the 5-halogen-substituted compounds 10, 11, and 12 were inactive. Compounds 10, 11, and 12 were active against both viruses at noncytotoxic concentrations. The activity of compound 11 was particularly noteworthy, being at least 10-fold more potent than acyclovir.     

Tissue detection of biomolecular predictors in breast cancer

One of the promises of modern biotechnology is to improve medical care by providing accurate diagnosis and targeted treatment to patients who will derive the maximum benefit. Delivery of this promise in the 21st century is the result of major advances in biotechnology over the past 20 years. Sequencing of the human genome and other high-volume data discovery has become possible, owing to relatively inexpensive computation power and automation. The same forces that drove the human genome project are now being focused on cataloging various disease processes at the DNA, RNA and protein levels. As these high-throughput technologies are entering the clinical care environment, the major task at hand is to integrate the complex data and derive clinically useful information. In spite of major breakthroughs in molecular approaches to the diagnosis and prognostication of cancer, there remain significant obstacles in applying these technologies to clinical samples. The time-honored conventional histopathology, for example, is still the backbone of tumor diagnosis and prognostication. The traditional fixation and processing methods are, however, rapidly losing ground, as they do not protect important tissue macromolecules. Formalin, the common universal fixative, is losing its place in histopathology. In addition to its toxicity, it alters macromolecules and renders the tissue unfit for most advanced molecular studies. This has prompted the use of fresh or fresh-frozen biopsy material for most biomolecular discoveries and clinical assays. This of course is impractical, or even impossible, in most clinical settings, particularly since tumors are being detected earlier and smaller. Also, many preneoplastic conditions are impossible to triage for freezing since their accurate diagnosis requires the use of the entire sample for detailed microscopic examination. The focus in this report is on breast cancer, where the value of the innovative approaches of the tissue detection of biomolecular predictors is examined. To this end, novel tissue handling platforms are introduced that are not only suitable for histological diagnosis, but allow the detection of tumor proteome and expression profiles on the same biopsy sample.     

Treatment of acute cutaneous leishmaniasis with intralesional injection of meglumine antimoniate: comparison of conventional technique with mesotherapy gun

Background The gold standard treatment of Old World leishmaniasis, a common tropical parasitic infestation, is intralesional meglumine antimoniate injection. Mesotherapy is a new minimally invasive method of administration of variable substances to the skin. Objective Comparison of the efficacy and adverse effects of treatment of leishmaniasis with intralesional injection of meglumine antimoniate using conventional method and mesotherapy method. Patients and methods Eighty‐five patients with proven leishmaniasis were recruited and randomly treated by one of the two methods, either by conventional injection or by mesotherapy administration weekly. Lesion characteristics were evaluated at every treatment session as well as 1 week, 1 month and 3 months after cessation of treatment. Results The improvement in lesions was similar in both groups, while it was noted sooner in mesotherapy group with less amount of drug usage (P = 0.005 and 0.016 respectively). Also, patients treated with mesotherapy experienced less pain severity (P = 0.005). Conclusion Mesotherapy is a safe and effective method of meglumine antimoniate injection for the treatment of cutaneous leishmaniasis and is less painful.     

Étude ethnobotanique de la flore médicinale dans la commune rurale d’Aguelmouss province de Khénifra (Maroc)

The present study should be set in the framework of valorization of medical plants and traditional knowledge’s from central middle Atlas of Morocco. Using 280 survey forms, hethnobotanical study was conducted during the months of June, July, August and September 2013 on the therapeutic uses of spontaneous medical plants in the seven tribal fractions that compose Aguelmouss municipality; this phase revealed the occurrence of 103 medicinal species which are divided into 43 families and 87 genera. The analyses results showed that six families commonly used by the population with a clear dominance of Lamiaceae. Also, species with very high frequency of use are Thymus willdenowii, Corrigiola telephiifolia Caralluma europaea et Juniperus oxycedrus. Furthermore, leaves are the most used part and the majority of remedies are prepared as a decoction. In terms of the treated disease, disorders of the digestive system ranks first with a rate of 38.9%.     

Health,safety, and environmental management system operation in contracting companies: A case study

Systematic and cooperative interactions among parent industry and contractors are necessary for a successful health, safety, and environmental management system (HSE-MS). This study was conducted to evaluate the HSE-MS performance in contracting companies in one of the petrochemical industries in Iran during 2013. Managers of parent and contracting companies participated in this study. The data collection forms included 7 elements of an integrated HSE-MS (leadership and commitment; policy and strategic objectives; organization, resources, and documentation; evaluation and risk management; planning; implementation and monitoring; auditing and reviewing). The results showed that mean percentage of the total scores in seven elements of HSE-MS was 85.7% and 87.0% based on self-report and report of parent company, respectively. In conclusion, this study showed that HSE-MS was desirably functioning; however, improvement to ensure health and safety of workers is still required.     

Analysis of 13 early failures of the mobile bearing Oxford phase III unicompartmental knee prosthesis

The use of unicompartmental knee arthroplasty appears to be increasing despite a significant number of early revisions. This study looks at a consecutive series of such procedures. We retrospectively reviewed thirteen patients who had a revision of a unicompartmental knee replacement between January 2003 and March 2008 inclusively. During the study period, a total of 141 UKAs were performed in the reporting unit, of those 9 were revised to TKA. The indication for revision to TKA was determined from clinical records and radiographs. All patients who underwent revision were followed up using Oxford Knee Score. No preoperative Oxford Knee Scores were available. The study group consisted of six men and seven women. The preoperative diagnosis was osteoarthritis in all cases. The mean follow-up time was 16.4 ± 10.7 months (range: 2–36 months). The mean age of the patients at time of revision was 60.8 ± 9.7 years (range: 50–77 years). All patients had undergone medial UKA. The mean time interval between primary surgery and revision surgery was 21.5 ± 13.4 months (range: 5–48 months). The indications for revision included loosening of the tibial and/or femoral component (n = 7), progression of osteoarthritis to lateral compartment (n = 2), unexplained medial knee pain (n = 2) patellofemoral symptoms (n = 1), and insert dislocation (n = 1). The mean postoperative Oxford Knee Score at the latest follow-up evaluation was 14 ± 6.5 (range: 5–26). For the majority of patients, UKA provides reliable and reproducible results. However, UKA is a demanding procedure that needs special experience and includes a risk of early failure.