Management of allergic fungal sinusitis with intracranial spread

Allergic fungal sinusitis (AFS) is a form of paranasal nasal disease if not managed early often involves bone destruction and extension into the orbit and anterior skull base. We present our study of patients with AFS with intracranial, exdradural extension. This study includes our experience of 26 patients with the histological and immunological diagnosis of AFS based on findings of branching septate fungi interspersed with eosinophilic mucin and Charcot-Leyden crystals without fungal invasion of soft tissue, with intracranial extension. All had erosion of bone, which was observed on computerized tomography (CT) scans, extending intracranially and eight had disease that additionally involved the lamina papyracea. The average age of patients in this study was 25 years (range 9–46). There were 20 male and 6 female patients. All patients were immunocompetent. Skin test against aspergillin showed all patients had Type 1 hypersensitivity. All patients underwent transnasal and/or transmaxillary endoscopic approaches for debridement and eight underwent orbital decompression. No patient underwent craniotomy for removal of intracranial extradural disease. No patient had a cerebrospinal fluid leak. Postoperatively, all 26 were treated with a course of corticosteroids. The follow-up period ranged from 2 to 5 years. We conclude AFS is a unique form of fungal disease that might mimic anterior skull base and paranasal sinus tumors. Most cases can be successfully managed with transnasal and/or transmaxillary endoscopic techniques.     

Neuroendocrine carcinoma of the ethmoid sinus

The paranasal sinuses are a rare site for neuroendocrine carcinoma (NEC). In contrast to the other regions, NEC of the sinuses has been reported to be recurrent and locally destructive. We report a case of NEC of the ethmoid sinuses. The patient was a 16-year-old Indian boy and was treated with radiation therapy to 6500 rad. He has been disease free for the past 5 years. All the cases reported to date were also reviewed.Adapted from a presentation at the annual meeting of the American Academy of Otolaryngology Head and Neck Surgery, Inc., Washington, D.C., 13–17 September 1992     

New norditerpenoid alkaloids from Aconitum falconeri

The roots of Aconitum falconeri have yielded two new norditerpenoid alkaloids, faleoconitine (1) and 3'-methoxyacoforestinine (2) along with the known compounds, karakoline, 3-hydroxy-2-methyl-4H-pyran-4-one, and 3,4-dimethoxymethylbenzoate, which have been isolated for the first time from this plant. The previously reported pseudaconitine (3) was also isolated. Compounds 1 and 3 were found to be moderate inhibitors of the enzyme acetylcholinesterase.     

Taraxacin, a new guaianolide from Taraxacum wallichii

A new guaianolide, taraxacin (1), and a known sesquiterpene ketolactone (2) have been isolated from an ethyl acetate-soluble part of a methanolic extract of Taraxacum wallichii. The structure of 1 was established using NMR, MS, and X-ray crystallographic methods. The (13)C NMR data of 2 is also being reported for the first time.     

Increased risk of second cancers following breast cancer: Role of the initial treatment

Objectives and methods.The risk of second primary malignancies (SMN) was studied in a cohort of 4,416 one-year survivors of a breast cancer. The role of the menopausal status and of the initial treatment modalities (surgery, radiotherapy, and chemotherapy) was investigated. Results.Excluding second primary breast cancer and non-melanoma skin cancer, a total of 193 (4.4%) patients developed a SMN between 1973 and 1992, compared with 136 expected (Standardised Incidence Ratio, SIR=1.4, 95% CI (1.2–1.6)). No trend towards either an increase or a decrease was noted in the SIR with time after treatment (p=0.2). The greatest increase in the relative risk concerned soft tissue cancers (SIR=13.0, 95% CI: 6.8–22.3), followed by leukaemia (SIR=3.1, 95% CI: 1.7–5.0), melanoma (SIR = 2.7, 95% CI: 1.4–4.8), kidney (SIR=2.5, 95% CI: 1.2–4.5), ovary (SIR=2.0, 95% CI: 1.2–3.1) and uterine tumours (SIR=1.9, 95% CI: 1.4–2.5). The SIR was 3.0 (95% CI 1.8–4.7) in women under 40 at the time of the breast cancer, 1.9 (95% CI : 1.4 – 2.4) in those aged 40–49 and 1.2 (95% CI 1.0–1.4) in those aged 50 or more. In the 2,514 women who had received radiotherapy as initial treatment without chemotherapy, the SIR for all SMN was 1.6 (95% CI: 1.1–2.3) fold higher than in those who had not received radiotherapy as initial treatment. Conclusion.In conclusion, this study confirms the increased risk of second malignancies in women treated for a breast cancer, and particularly in those who were younger at the time of treatment for breast cancer. Our results also suggest that radiotherapy may play a role in the onset of these second lesions.     

The role of microembolisation in cerebral injury as defined by functional magnetic resonance imaging.

OBJECTIVE: Cerebral injury, in both overt and subtle forms, is common following cardiac surgery. Current methods of assessment, most commonly neuropsychological testing, have several limitations and do not accurately define the anatomical and functional injury that occurs. We have assessed the degree of cerebral injury following on-pump and off-pump cardiac surgery using functional magnetic resonance imaging and correlated this with the severity of microembolism as measured by transcranial Doppler ultrasound. METHODS: Sixteen patients undergoing cardiac surgery (8 off-pump coronary artery bypass grafting (CABG), 4 on-pump CABG and 4 open-heart surgery) underwent functional magnetic resonance imaging of the brain pre-operatively and 4 weeks post-operatively. The functional magnetic resonance images demonstrated brain activation during performance of a verbal working memory paradigm. Each patient had continuous transcranial Doppler monitoring intraoperatively using a recently validated technique (multirange, multifrequency Doppler) that allows rejection of artefacts and separation of gas and solid microemboli. Covariate analysis of pre- and post-operative functional magnetic resonance images was performed to correlate local mean signal intensity change with the extent of gas and solid microembolism. RESULTS: The median number of microemboli was 34 (range 10-176) in the off-pump group, 229 (range 127-314) in the on-pump CABG group, and 1220 (range 874-1261) in the open-heart group (P<0.05). The proportion of solid microemboli was significantly lower in the off-pump group in comparison to the on-pump CABG and open-heart groups (9 vs. 25 vs. 20%, respectively, P<0.01). Comparison of pre- and post-operative functional magnetic resonance images demonstrated an overall reduction in task-associated activation in the post-operative period. However, and paradoxically, in certain specific regions of interest there was an increase in the signal intensity which correlated with the total number of microemboli (r=0.9, P<0.01). CONCLUSIONS: Patients undergoing on-pump surgery have a higher degree of gas and solid microembolism which correlates with post-operative cerebral functional MRI activation. As activation with functional magnetic resonance imaging of the brain is known to be sensitive to a wide range of insults, it may prove to be a useful marker of perioperative cerebral injury that could help in the evaluation of potential cerebroprotective strategies.     

Stimulation of phospholipase D by phorbol esters and ionomycin in bovine corneal epithelial cells.

This study was performed to determine the effects of phorbol esters and ionomycin on phospholipase D (PLD) activity in bovine corneal epithelial cells (BCEC). The cells were prelabeled with [3H]myristic acid and incubated for specific time intervals with various test agents in the presence and absence of ethanol. The PLD activity was assayed by monitoring the formation of labeled phosphatidylethanol ([3H]PEt) in [3H]myristate labeled cells. In the absence of ethanol, 1 microM phorbol 12-myristate 13-acetate (PMA) increased the formation of labeled phosphatidic acid ([3H]PA) with no significant effect on the radioactivity of [3H]PEt. In the presence of 85 mM ethanol, whereas there was only a small further increase in [3H]PA, the formation of [3H]PEt was increased by several-fold, demonstrating activation of PLD by the phorbol ester. The effects of PMA were time- and dose-dependent, and were mimicked by phorbol 12,13-dibutyrate. The inactive phorbol derivatives, 4-alpha-phorbol, 4-alpha-phorbol 12,13-didecanoate, 4-alpha-phorbol 12-myristate 13-acetate and 4-alpha-phorbol 12,13-dibutyrate, were without effect. Short-time (30 min) incubation of BCEC with staurosporine or H-7, or prolonged (20 hours) incubation with PMA rendered the cells less sensitive to subsequent treatment with PMA, suggesting that activation of PLD in the cells is mediated by protein kinase C (PKC). Addition of 20 microM ionomycin in the presence of ethanol also increased the formation of [3H]PA and [3H]PEt in a time- and dose-dependent manner. Co-presence of ionomycin and PMA at submaximal concentrations in the incubation medium resulted in increased formation of [3H]PA and [3H]PEt which was less than their individual effects combined, indicating a lack of synergism between Ca2+ and PMA in activating PLD. Incubation of BCEC with staurosporine resulted in significant inhibition of ionomycin-induced production of [3H]PEt, suggesting that in addition to direct activation of PLD by Ca2+, the enzyme is probably stimulated by sequential activation of PLC (producing diacylglycerol) and PKC following the ionomycin addition. We conclude that BCEC possess PLD which is stimulated by PKC as well as elevated intracellular Ca2+.     

Polypropylenimine dendrimer-induced gene expression changes: the effect of complexation with DNA, dendrimer generation and cell type

Polypropylenimine (PPI) dendrimers appear attractive non-viral vectors for the delivery of genes, antisense oligonucleotides, and small interfering RNA (siRNA). However, the effects of these synthetic gene delivery vectors on global gene expression are poorly understood. Here we have examined the toxicogenomics of generation 2 (DAB-8) and generation 3 (DAB-16) PPI dendrimers in two human cell lines. At concentrations and treatment protocols routinely used for gene and oligonucleotide transfection, PPI dendrimers alone elicited marked changes in endogenous gene expression in A431 epithelial cells. The extent of PPI-induced gene changes appeared to be dependent on the dendrimer generation as the number of genes affected was greater with G3 compared to G2 PPI dendrimers in A431 cells. The signature of DAB16-induced gene changes in A549 cells was different to those elicited in A431 cells implying a strong dependence on cell type. The DAB-16 polymer complexed with DNA (dendriplexes) also elicited marked gene expression changes in A549 cells but with a signature that was different from the polymer alone implying that dendriplexes are "recognised" by cells as chemical entities that are distinct from the polymer alone. Alterations in expression of a variety of gene ontologies were observed including those involved in defence responses, cell proliferation and apoptosis. Although there was a tendency for increased DNA damage in cells treated with DAB16 alone or its DNA dendriplexes as detected by the COMET assay, these differences were not statistically significant. These data show for the first time that PPI-dendrimers, separate from their capability as transfection reagents, can intrinsically alter the expression of many endogenous genes that could potentially lead to them exerting multiple biological effects in cells. The impact and consequences of polymer-induced gene changes should guide their rational use as delivery systems for gene-based therapeutics.