Synthesis of 3-acetoxyazetidin-2-ones and 3-hydroxyazetidin-2-ones with antifungal and antibacterial activity

The synthesis of a series of 3-acetoxyazetidin-2-ones 3a–n and 3-hydroxyazetidin-2-ones 6a–j is reported together with the antibacterial and antifungal evaluation of these compounds. An additional series of 3-acetoxyazetidin-2-ones 11a–h which possess a free carboxylic acid group on the N-1 aryl ring were obtained by treatment of suitably substituted Schiff bases 10a–h with acetoxyacetyl chloride. The novel bicyclic structures 7-acetoxy-6-phenyl-5-thia-1-azabicyclo[4.2.0]octan-8-one 13 and 7-hydroxy-6-phenyl-5-thia-1-azabicyclo[4.2.0]octan-8-one 14 were also obtained. Many of the compounds displayed antifungal activity in vitro when evaluated against the pathogenic fungi Cryptococcus neoformans, Candida albicans, Candida tropicalis, Candida parapsilosis, Candida glabrata, and Trichosporon cutaneum, while 3-acetoxyazetidin-2-ones 11a–h containing a free carboxylic acid group on the N-1 aryl ring displayed antibacterial activity against Staphylococcus aureus, Proteus vulgaris, Pseudomonas aeruginosa, Bacillus subtilis, Klebsiella aerogenes and Escherischia coli.     

Immediate hypersensitivity to Parthenium hysterophorus. II. Clinical studies on the prevalence of parthenium rhinitis

The airborne pollen of the South American weed, Parthenium hysterophorus (American feverfew), accidentally introduced into India was found to be responsible for severe allergic rhinitis. A random clinical survey conducted on 2035 residents of Bangalore city with the aid of questionnaires and skin tests revealed that 7.1% of the study population was suffering from allergic rhinitis due to exposure to Parthenium pollen. Skin-prick tests performed on 1294 clinic patients suffering from nasobronchial allergy during the past 4 years have also shown that 42.5% were sensitive to Parthenium pollen. IgE and IgG antibodies specific for Parthenium pollen allergens were demonstrable in the sera of Parthenium-sensitive rhinitis patients. The specificity of these antibodies to Parthenium allergens was established by ELISA. A 7- to 11-fold higher stimulation was observed when lymphocytes from two Parthenium-sensitive rhinitis patients were treated in vitro with Parthenium pollen extract. To our knowledge, nowhere in the world has such a high incidence of allergic rhinitis due to a single pollen ever been reported.     

t(1;3)(p36;q21) in acute nonlymphocytic leukemia: a new cytogenetic- clinicopathologic association

A number of specific chromosomal abnormalities have been associated with distinctive clinical and/or morphological subtypes of acute nonlymphocytic leukemia (ANLL) in recent years. We have studied three patients with ANLL and t(1;3)(p36;q21). Each had weakness as their major complaint, a moderately severe anemia and, for ANLL, a relatively high platelet count. All three demonstrated abnormalities of the megakaryocytic, erythroid and granulocytic lineages. Most striking was the dysmegakaryocytopoiesis. The blasts in all three patients showed relatively few azurophilic granules, one to four prominent nucleoli, and rare peroxidase positivity. No patient had Auer rods. No patient responded to standard chemotherapy regimens. The data suggest that t(1;3)(p36;q21) identifies a new cytogenetic-clinicopathologic subtype of ANLL.     

Topical transforming growth factor-beta3 in the prevention or alleviation of chemotherapy-induced oral mucositis in patients with lymphomas or solid tumors

Transforming growth factor (TGF)-beta3 has been hypothesized to prevent or alleviate oral mucositis (OM) in cancer patients receiving high-dose chemotherapy (CT). Two double-blind, placebo-controlled, multicenter, phase II studies of TGF-beta3 were initiated in the United States, Europe, and Argentina in patients with lymphomas or solid tumors who were receiving highly stomatotoxic CT regimens. Patients were to apply 10-mL mouthwash applications of TGF-beta3 (25 microg/mL) or placebo four times daily (or twice daily) 1 day before and all days during CT. The patients were subsequently evaluated for OM incidence, severity, and duration using National Institute of Cancer Common Toxicity Criteria (NCI-CTC) criteria and an objective scoring system (1). After the start of the trials, negative results from new preclinical studies suggesting suboptimal formulation and/or dosing led to an interim analysis of the ongoing clinical trials. One hundred fifty-two patients from the combined studies were included in the interim analysis, with 116 patients on the TGF-beta3 four times daily and placebo arms. Most (72%) patients had breast cancer, 22% had lymphomas, and 6% had other solid tumors. Although 98% (149 of 152) of patients experienced adverse events, only 14% (22 of 152) experienced events that were judged as possibly or probably related to the study drug (primarily gastrointestinal symptoms). No clinically relevant differences were seen between the treatment and placebo arms regarding safety, nor was there evidence for systemic absorption of TGF-beta3. Finally, there was no advantage of TGF-beta3 treatment regarding the incidence (TGF-beta3 four times daily versus placebo [46% versus 47%]), onset, or duration of NCI-CTC grade 3 or 4 OM. For this dose, formulation, regimen. and patient population, TGF-beta3 was not effective in the prevention or alleviation of CT-induced OM.     

Immunopathological studies on the cutaneous lesions in sarcoidosis

We examined the immunohistology of the cutaneous granulomas in sarcoidosis. By direct immunofluorescence immunoglobulin deposits were found in the skin lesions of 5 to 8 patients. These consisted of IgM within blood vessel wall (5 patients), IgM at the epidermal-dermal junction (2 patients) and IgG within and around the granuloma (2 patients). A fibrin network was present within the granulomas. Biopsy of a Kveim test site but not of uninvolved skin or of an erythema nodosum lesion showed similar immunofluorescence findings. Sheep erythrocytes sensitized with IgG antibody adhered to epithelioid cells within the granuloma indicating the presence of surface Fc receptors. At the periphery of the granulomas were B-lymphocytes. These findings are similar to those described in nodal and pulmonary sarcoid granulomas, and suggest that humoral antibodies may be important in the pathogenesis of the sarcoid granuloma.     

Is the male involved in the aetiology of ectopic pregnancy?

We have previously observed a low incidence of ectopic pregnancies in couples having gamete intra-Fallopian transfer (GIFT) with donated spermatozoa. Based on findings in both animal and human models, we proposed the hypothesis that sperm defects may be associated with the expression of paternal genes which cause abnormal early embryo development and predispose the embryos to interact inappropriately with the genital tract epithelium, and so increase the risk of an ectopic implantation. To both confirm and extend the initial observation, GIFT and in-vitro fertilization (IVF) pregnancies entered on the Australian and New Zealand national database between 1979 and 1993 were analysed with regard to the incidence of ectopic pregnancy. There was an increased risk of ectopic pregnancy for IVF relative to GIFT and when spermatozoa from the male partner were used rather than donor spermatozoa. However, when couples were categorized with respect to the aetiology of their infertility, we were unable to show a significant association between ectopic pregnancy and whether spermatozoa from the male partner or a donor were used. We have therefore been unable to confirm a direct association between the source of spermatozoa and ectopic pregnancy.      

Equivocal mammographic findings: evaluation with spot compression

Seventy-five spot compression views of equivocally suspicious lesions detected at routine mammographic examination of 72 women were reviewed in this retrospective study. Sixty-five of the 75 lesions appeared less suspicious on spot compression views, two did not change, and eight appeared more suspicious. Biopsy findings confirmed that the eight more suspicious lesions were cancer. The adjunctive use of spot compression helped characterize equivocal findings seen on routine mammographic views and improved the accuracy of mammographic interpretation.     

PET detection of viable tissue in myocardial segments with persistent defects at T1-201 SPECT

To assess myocardial glucose metabolism and perfusion in 142 myocardial segments with defects seen at thallium-201 single photon emission computed tomography (SPECT), 27 studies with positron emission tomography (PET) utilizing nitrogen-13 ammonia and fluorine-18 deoxyglucose were performed in 26 patients. Myocardial infarction was defined on the basis of concordant reductions in segmental perfusion and glucose utilization; myocardial ischemia, on the basis of preservation of glucose utilization (metabolic viability) in segments with hypoperfusion at rest. Of the 142 segments analyzed, 101 had fixed defects, 31 had partially reversible defects, and ten had completely reversible defects. Preserved glucose utilization was identified in 47 (46.5%) of the segments with fixed defects and 20 (64.5%) of the segments with partially reversible defects. Of the ten segments with completely reversible defects, five (50%) were normal, and five (50%) exhibited ischemia at PET. Visual improvement in a persistent thallium defect at delayed imaging was not associated with residual glucose metabolic activity. Thus, PET can be used to detect glucose metabolic activity in a significant proportion of myocardial segments with fixed or partially redistributing defects seen at thallium SPECT, which suggests that the extent of tissue viability in patients with ischemic heart disease is underestimated at thallium scintigraphy.     

Patient immobilization during CT for treatment planning of head and neck cancer

Immobilizers are described that have been used during computed tomography (CT) to ensure reproducibility of patient position during all phases of radiation treatment planning and delivery. The immobilizer causes no degradation or artifact on CT images; hence, the value of the images in radiation treatment planning is not compromised.