Medical mycology in the UK: time to stop the dry rot.
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Career Choice↗
Biomedical subjects
A Hamilton
Publications and source records attributed to A Hamilton.
The third-generation non-steroidal aromatase inhibitors: a review of their clinical benefits in the second-line hormonal treatment of advanced breast cancer.
Three new aromatase inhibitors have recently completed phase III evaluation as treatment of metastatic breast cancer in post-menopausal women whose disease has progressed despite tamoxifen therapy: anastrozole (ARIMIDEX, Zeneca), letrozole (FEMARA, Novartis) and vorozole (RIVIZOR, Janssen). All belong to the third generation of non-steroidal aromatase inhibitors, and each is superior to previous generations in terms of potency and selectivity. The trials that have been performed compare each agent to megestrol acetate, and letrozole and vorozole to aminoglutethimide. Although the studies are not directly comparable due to differing study designs and patient populations, it has been demonstrated each of these drugs provides single agent, once-daily, oral palliation of hormone-responsive, post-menopausal metastatic breast cancer. Letrozole is clearly more effective than megestrol acetate, and anastrozole and vorozole are possibly so. All three are better tolerated than the progestin, particularly in terms of weight gain. Both letrozole and vorozole are significantly more effective, and better tolerated than aminoglutethimide. Overall, this most recent generation of aromatase inhibitors is a clear improvement on our current standard second-line therapies. In 1999, tamoxifen remains the first choice in the hormonal therapy of breast cancer. Following tamoxifen failure, the optimal second-line hormonal therapy remains undefined, but aminoglutethimide and megestrol acetate are no longer optimal therapy in this setting. The third-generation non-steroidal aromatase inhibitors must now be compared to each other, to the steroidal aromatase inhibitors, to the pure anti-oestrogens, and to tamoxifen.
Aged↗
Fluorescent detection techniques for real-time multiplex strand specific detection of Bacillus anthracis using rapid PCR.
Speed is a key area in our development of PCR assays for Bacillus anthracis. We believe that the strand specific detection of amplicons within 10 min is a realistic goal and that this will be achieved through fluorescent in-tube assays. We have used the Idaho LightCycler to study and develop candidate assays for B. anthracis. New strand specific fluorescent methods have been developed and a number of formats have been studied for speed and sensitivity. Internal controls have been developed as a method of improving our assay confidence. In this communication we will introduce the field of rapid PCR whilst discussing previous work in the areas described above, the development of our own rapid assay and a novel internal control system for B. anthracis. This work used PCR assays and hardware that are either commercially available, or have been previously described in open literature publications.
Animals↗
SPIKEII: an integrate-and-fire AVLSI chip.
We present the SPIKEII chip, an integrate-and-fire neural network chip with programmable synapses implemented in analogue VLSI. It is the successor to the SPIKEI chip. We describe the circuitry, and show some results using networks of integrate-and-fire neurons.
Action Potentials↗
Current drug therapy for multiple myeloma.
Recent years have witnessed tremendous advances in the molecular pathogenesis and management of multiple myeloma. Standard chemotherapy (melphalan and prednisone; MP) has been the mainstay of treatment of multiple myeloma for about 3 decades. However, it is no longer considered the 'gold standard', particularly for those patients who will subsequently undergo intensive chemotherapy with autologous or allogeneic peripheral blood stem cell (PBSC) or bone marrow transplantation (BMT), or for patients with refractory myeloma. A variety of induction combination chemotherapy regimens have been developed, some of which have demonstrated an improved response rate and duration and a superior 5-year survival rate when compared with standard chemotherapy. The early use of high dose chemotherapy with autologous PBSC support or BMT has significantly increased the complete remission rate, and has prolonged event-free sur vival and overall survival. Allogeneic bone marrow or PBSC transplantation may be a good option for selected patients with poor prognostic features. The role of interferon-alpha in multiple myeloma is still inconclusive despite many years of clinical evaluation. The clinical application of chemosensitising agents that can inhibit P-glycoprotein (P-gp) expression and function, and particularly the development of more potent P-gp modulators such as valspodar (PSC 833) and elacridar (GF120918) has made it possible to reverse multidrug resistance in some refractory patients and to enhance the efficacy of chemotherapeutic agents. Immunotherapeutic approaches to purging of autologous bone marrow or PBSC, or as adjuvant therapy for minimal residual disease, show great promise. Finally, a number of new therapies specifically designed to treat many of the complications of multiple myeloma are improving clinical outcomes and quality of life for these patients.
Antineoplastic Combined Chemotherapy Protocols↗
Predicting extracapsular extension of prostate cancer in men treated with radical prostatectomy: results from the population based prostate cancer outcomes study.
PURPOSE: We investigated whether clinical information routinely available in community practice could predict extracapsular extension of clinically localized prostate cancer in men undergoing radical prostatectomy. MATERIALS AND METHODS: We examined prostate cancer outcomes in a population based sample of 3,826 patients with primary prostate cancer in 6 regions of the United States covered by the Surveillance, Epidemiology, and End Results program. Stratified and weighted logistic regression was used to identify predictors of and probabilities for extracapsular extension of clinically localized tumors treated with radical prostatectomy. RESULTS: Nearly 47% of men undergoing radical prostatectomy had extraprostatic extension. The strongest predictors were elevated prostate specific antigen (PSA) greater than 20 versus less than 4 ng./ml. (odds ratio 5.88, 95% confidence interval 2.90 to 11.15), Gleason score greater than 8 versus less than 6 (1.73, 1.04 to 2.87) and age greater than 70 versus less than 50 years (1.91, 0.98 to 3.70). Ethnicity and region were not associated with increased risk of extraprostatic extension. A nomogram developed from our model predicts extracapsular extension ranging from 24% in men younger than 50 years with PSA less than 4 ng./ml. and a Gleason score of less than 7 to 85% in those 70 years old or older with PSA greater than 20 ng./ml. and a Gleason score of 8 or more. If prostatectomy were limited to patients with less than 60% probability of extraprostatic extension based on the nomogram, 95% of those with organ confined cancers would undergo definitive surgery and 18% of those with extracapsular extension would be spared the morbidity of surgery. CONCLUSIONS: In a population based analysis of prostate cancer practice patterns PSA, Gleason score and age are clinically useful predictors of extracapsular extension. Although extracapsular extension may be an imperfect predictor of cancer outcomes, our nomogram provides more realistic probabilities for extracapsular extension than those based on institutional series.
Aged↗
Neuromorphic systems. Introduction.
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Animals↗
Primary synovial chondromatosis: a clinicopathologic review and assessment of malignant potential.
This is a clinicopathologic review of 53 cases of primary synovial chondromatosis covering a period of 30 years. The average age at presentation was 41 years (range, 17 to 64 years) with a male/female preponderance of 1.8:1. The condition was always monarticular, the most common site being the knee joint (70%) followed by the hip (20%). Degenerative joint disease was well established in three patients (5%), all occurring in the hip. Nine patients suffered recurrences (15%), including three that became malignant. There was no relationship between the age and site of the lesion, nor between the degree of cellularity of the cartilage and age or site. However, there was an association between cellularity of the cartilage and the extent of calcification and ossification--highly cellular lesions were poorly calcified and ossified, but heavily calcified lesions were usually of relatively low cellularity. There was no relationship between extent of calcification and ossification and the age of the patient. Three patients suffered malignant change representing a relative risk of 5%, much higher than that quoted in other series. This suggests that primary synovial chondromatosis has a significant potential for malignant change.
Adolescent↗
Pranlukast, a cysteinyl leukotriene receptor antagonist, attenuates allergen-induced early- and late-phase bronchoconstriction and airway hyperresponsiveness in asthmatic subjects.
BACKGROUND: The cysteinyl leukotrienes (cysLTs) have been implicated in the pathogenesis of allergen-induced airway responses. The purpose of this study was to evaluate the effects of pretreatment with the cysLT receptor antagonist pranlukast on allergen-induced early asthmatic responses (EARs) and late asthmatic responses (LARs) and on allergen-induced airway hyperresponsiveness (AHR). METHODS: Ten atopic, nonsmoking patients with mild asthma and previously demonstrated early- and late-phase allergen-induced asthmatic responses participated in a double-blind, placebo-controlled, cross-over study, comparing treatment with either 450 mg pranlukast given twice daily or placebo for 5.5 days. A methacholine challenge was performed before administration of medication, and the result was expressed as the PC20. An allergen inhalation challenge was performed on the morning of the fifth day of treatment 2 hours after administration of medication. Methacholine challenges were also performed 2 hours after medication on days 4 and 6 (24 hours before and 24 hours after allergen administration) to examine allergen-induced AHR. RESULTS: Pranlukast attenuated allergen-induced early responses, late responses, and AHR. The mean (SEM) maximal percent fall in FEV1 from baseline during the early response was 30.0% (5.1%) during placebo treatment and 15.5% (3.5%) during pranlukast treatment (mean difference, 14.5%; 95% confidence interval [CI], 5.3 to 23.7; P = .007), with a mean protection afforded by pranlukast of 48.3%. The mean maximal percent fall in FEV1 during the late response was 34.7% (5.3%) during placebo treatment and 24.0% (4.4%) during pranlukast treatment (mean difference, 10.7%; 95% CI, 4.1 to 17.3; P = .006), with a mean protection afforded by pranlukast of 30.8%. The mean allergen-induced shift in PC20 was -1.76 (0.32) doubling doses during placebo treatment and -0.38 (0.31) doubling doses during pranlukast treatment (mean difference, -1.38 doubling doses; 95% CI, 0.44 to 2.32; P = .012), with a mean protection afforded by pranlukast of 78.4%. CONCLUSION: These results demonstrate that pranlukast can attenuate allergen-induced early and late airways responses and AHR and adds further support for an important role for the cysLTs in mediating allergen-induced asthmatic responses.
Adolescent↗
The use of stereotactic radiosurgical boost in the treatment of medulloblastomas.
PURPOSE: Starting in 1992, we began using a stereotactic radiosurgical (SRS) boost for the treatment of medulloblastomas. Four patients ranging in age from 7 to 42 years old have since been treated and are the subject of this retrospective study. METHODS AND MATERIALS: All patients were initially treated with a maximally debulking surgery and external beam radiotherapy, which were then followed by a stereotactic radiosurgical boost using a modified 6 MeV linear accelerator. Radiosurgical boost doses ranged from 4.50 to 10.0 Gy. Target volumes ranged from 1.1 to 8.1 cc. The procedure was well tolerated with minimal acute toxicities. RESULTS: All four patients are alive without evidence of recurrence (at 8 to 35 months). Acute nausea and vomiting was elicited during the radiosurgical procedure in the first patient treated. We have since begun premedicating patients with antiemetics or treating under general anesthesia. Late complications consisted of panhypopituitarism in one patient, which was thought to be attributable to the previous course of whole-brain radiotherapy. We have not observed any incidence of radionecrosis in this small cohort of patients. CONCLUSIONS: Our preliminary results with the use of radiosurgery for medulloblastomas are optimistic, and we would like to suggest the inclusion of a radiosurgery boost in future clinical trials for treatment of this disease.
Adult↗
Anaesthesia for phaeochromocytoma in pregnancy.
PURPOSE: Phaeochromocytoma in pregnancy is a rare occurrence. Details of the anaesthetic are even more rarely reported. Our purpose is to describe our management with reference to previous reports. CLINICAL FEATURES: A 31-yr-old woman underwent resection of a phaeochromocytoma at seven weeks gestation. Preoperative preparation included 2 mg prazosin p.o. bid and 40 mg propranolol p.o. bid. A balanced anaesthetic technique including 5 mg midazolam, 1500 micrograms alfentanil, 35 micrograms sufentanil, nitrous oxide and isoflurane was used. Blood pressure was controlled with 3.4 g magnesium and 2437 micrograms nitroglycerin. There were no episodes of hypertension intraoperatively. The patient made an uneventful recovery and delivered a normal baby at 37 wk gestation by caesarean section. CONCLUSION: Anaesthesia for resection of a phaeochromocytoma in early pregnancy can be successfully managed with preoperative alpha and beta sympathetic blockade and a balanced anaesthetic technique using magnesium as the main intraoperative hypotensive agent.
Adrenal Gland Neoplasms↗
Comparison of Ho:YAG versus Nd:YAG thoracoscopic laser treatment of pulmonary bullae in a rabbit model.
OBJECTIVE: To determine the relative efficacy and morbidity of Ho:YAG versus Nd:YAG laser treatment of bullous lung disease in an animal model. SUMMARY BACKGROUND DATA: Laser coagulation procedures for treatment of emphysematous pulmonary bullae and heterogeneous emphysema continue to evolve. The role of lasers in lung volume reduction surgery remains controversial due to issues of relative efficacy and morbidity. The Nd:YAG laser is most commonly used for these procedures. We hypothesized that the shallower penetration of the Ho:YAG laser may be better suited for laser bullae coagulation and emphysema lung volume reduction with increased efficacy and reduced lung injury. METHODS: Thirty New Zealand White rabbits (15 normal rabbits; 15 with bullous lung disease) were evaluated with Ho:YAG compared to Nd:YAG laser exposures. Bullae were coagulated by either Ho:YAG or Nd:YAG treatment. In all animals (bullous-induced and normals), unaffected lung tissue in the upper lobes and contralateral lungs were treated with 5 spot exposures of Nd:YAG and Ho:YAG, each to assess depth of lung injury. Animals were sacrificed at Days 0, 7, and 21 and their lungs were examined histologically. RESULTS: Ho:YAG and Nd:YAG exposures caused equivalent lung injury to normal lung tissue. In the acute phase, parenchymal necrosis depth was similar for both Ho:YAG and Nd:YAG (850 +/- 273 microns vs. 900 +/- 270 microns respectively, p = 0.7). By Day 7, lung necrosis depth was 925 +/- 133 microns Ho:YAG vs. 1225 +/- 235 microns Nd:YAG (p = 0.33), and lung fibrosis depth was 300 +/- 134 microns Ho:YAG vs. 558 +/- 127 microns Nd:YAG (p = 0.11). By Day 21, pulmonary parenchymal necrosis was not seen. Pleural fibrosis depth was maximal at Day 21, reaching 250 +/- 102 microns for Ho:YAG vs. 300 +/- 156 microns Nd:YAG (P = 0.88). Pleural necrosis depth was 67 +/- 42 microns Ho:YAG vs 48 +/- 34 microns Nd:YAG (p = 0.42) on Day 7 and resolved by Day 21. During surgical coagulation procedures, the Ho:YAG laser was dramatically more efficient in coagulating bullae. The Ho:YAG laser required less exposure at equivalent power and resulted in immediate desiccation of bullae, in sharp contrast to the Nd:YAG laser. CONCLUSIONS: Because the Ho:YAG was more effective and did not result in more acute lung injury than the standard Nd:YAG laser in this study, Ho:YAG lasers may have improved potential for laser treatment of bullae or lung volume reduction surgery (LVRS) compared to Nd:YAG lasers.
Animals↗
Photodynamic therapy for antifibrosis in a rabbit model of filtration surgery.
BACKGROUND AND OBJECTIVE: The purpose of this pilot study was to investigate the use of photodynamic therapy (PDT) using tin ethyl etiopurpurin (SnET2) as an adjunctive antifibrotic therapy for filtering surgery in a rabbit model. MATERIALS AND METHODS: The pharmacokinetics of SnET2 were established by intravenous (1 mg/kg) and subconjunctival (25, 50, or 75 micrograms) injections and compared with controls. Intravenous and subconjunctival SnET2 injections were given prior to posterior lip sclerectomies followed by postoperative laser irradiation (664 +/- 7 nm; 100 mW/cm2; 30 J/cm2). Antifibrotic efficacy was established by clinical response and histologic examination. RESULTS: After subconjunctival injections, large areas of avascular conjunctiva were produced and filtering bleb survival was prolonged. No effect was found for intravenously administered photosensitizer followed by light irradiation. CONCLUSIONS: PDT may be an alternative antifibrotic therapy for filtration surgery that does not use chemotherapeutic agents or ionizing radiation. Multiple parameters (light, drug dose, irradiation area) may be manipulated to improve predictability of the antifibrotic effect.
Animals↗
[A study of cerebral maturity by means of quantitative analysis of the electroencephalogram].
INTRODUCTION AND OBJECTIVE: The objective of this study is to evaluate cerebral maturity by means of quantitative analysis techniques applied to the electroencephalogram (EEG). MATERIAL AND METHODS: A transversal study of cerebral maturity was carried out in 403 persons who had undergone an EEG. A previous pilot study had been carried out of 103 persons. A series of spectral parameters of the EEG were selected so that all those studied were in the most similar conditions possible. Different frequency bands were analyzed choosing the one with best discrimination of the maturity aspect. Classification of the different levels of cerebral maturity was done with the help of multivariant analysis. The value of the median of the frequencies and the spectrum of relative potencies at the moment when a frequency band is at a maximum are the parameters which evolve best with age and best discriminate maturity Spectral analysis allows selection of the frequency bands most suitable to the problem. Working with two frequency bands is sufficient to evaluate cerebral maturity. RESULTS: The variables obtained in the occipital channels were sufficient for evaluation of cerebral maturity. Those of the right hemisphere were more significant for diagnosis. The occipital channels are the most relevant in the study of cerebral maturity. CONCLUSIONS: The neuronal network is the most efficient classifier for classification of different groups of maturity The next most efficient method is by quadratic discriminant analysis. Consideration of the variables, taking into account the factors of stability and regularity of the EEG signals improves discrimination with respect to the average of those recorded during the entire procedure.
Adolescent↗
Synthesis and properties of DNA-PNA chimeric oligomers.
Adenine, thymine and cytosine PNA monomers have been prepared using 3-amino-1,2-propanediol as a starting material. The benzoyl group was used to protect the exocyclic amines of the heterocyclic bases of A and C PNA monomers and the backbone primary amine was protected with the monomethoxytrityl group. The thymine and cytosine PNA monomers were used in conjunction with standard DNA synthesis monomers to produce chimeric PNA DNA (PDC) oligomers. Ultraviolet melting studies confirmed that these oligomers form stable hybrids with complementary DNA strands and that mismatches in the DNA but more so in the PNA sections lead to duplex destabilisation.
Chemistry, Organic↗
Tuberculosis in the United Kingdom. Coverage by selective neonatal BCG vaccination should be monitored.
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BCG Vaccine↗
Animal model for thoracoscopic laser ablation of emphysematous pulmonary bullae.
BACKGROUND AND OBJECTIVE: Thoracoscopic laser techniques have been described for treatment of pulmonary bullae. Clinical application of this procedure has proliferated despite limited data regarding efficacy or optimal techniques. The objective of this study was to develop an animal model for investigating laser treatment of bullous lung disease. STUDY DESIGN/MATERIALS AND METHODS: Sixty-two New Zealand White rabbits (3-5 kg) were injected intravenously with 0.35 cc sterile-filtered Sephadex G-100 beads (1 g/100 cc suspension). Three hours later, rabbits were anesthetized, intubated, and 10 cc 0.7% heat-treated or 1% untreated carrageenan solution was instilled endotracheally into a catheter wedged in a mainstem bronchus. RESULTS: Bullae formed over 4-6 weeks in 33% of the animals treated with 0.7% heat-treated carrageenan, and 90% of animals receiving 1% untreated carrageenan (P < 0.005) as demonstrated by serial thoracoscopy. Thoracoscopy was performed at 6-8 weeks using 5 mm trocars under general anesthesia and mechanical ventilatory support. Animals developed pulmonary bullae ranging in size from 0.5 to 2 cm. Bullae were ablated under thoracoscopic visualization using a CO2 laser with a 4 mm OD rigid probe and short focal length in a defocused mode, or an Nd:YAG laser with a 0.4 mm diameter flexible fiberoptic probe. Animals recovered quickly following thoracoscopy. CONCLUSION: We have successfully developed an animal model for thoracoscopic laser ablation of emphysematous pulmonary bullae. This animal model should be useful in investigating treatment of bullous lung disease in humans.
Animals↗