Biomedical subjects
Publications and source records attributed to D Hughes.
A 38-year-old woman presented at 30 weeks gestation with bi-temporal upper quadrantanopia. MRI showed appearances typical of a pituitary macroadenoma. It was agreed that pituitary decompresssion would only be indicated if the visual field defect worsened. MRI imaging 2 weeks postdelivery showed complete resolution of the pituitary lesion.
A five-year-old domestic longhaired cat was evaluated for a seven-day history of worsening respiratory distress. Serum analysis for feline leukaemia virus antigen was positive. Pleural effusion was detected on thoracic radiographs and echocardiography revealed a pericardial effusion and cardiac tamponade. Cytological evaluation of the pleural and pericardial effusions showed lymphoblastic cells indicative of disseminated lymphoma. Following thoracocentesis and pericardiocentesis, the cat was treated for lymphoma using the University of Wisconsin-Madison chemotherapy protocol. The cat was sent home after three days and, at the time of writing (six months after initial presentation), was still symptom free. To the authors' knowledge, this is the first report confirming pericardial effusion and cardiac tamponade in the cat as a direct result of an extranodal lymphoma with cytological evidence of neoplastic cells in the pericardial fluid.
BMS-207940, a potent endothelin receptor antagonist, exists as rapidly interconverting atropisomers. The plasma interconversion t(1/2) is approximately 2.5 hours at 400 microg/mL under room temperature and decreases to < 0.1 hours at 20 microg/mL, making it extremely difficult to conduct pharmacokinetic studies of individual atropisomers. The pharmacokinetics of the 50/50 racemate of BMS-207940 in humans were reasonably described by a one-compartmental model with an apparent terminal elimination t(1/2) of 15 hours. Given the above rates, simulations were conducted based on a one-compartmental model to explore the possible range of individual rates of atropisomer elimination and potential difference in plasma exposure to the two atropisomers. Simulations demonstrated that the elimination rates of the individual atropisomers are bounded between 0 and 0.046 h(-1) and between 0.046 and 0.092 h(-1), respectively. The estimation of the upper bounds for atropisomer elimination rate constants is robust and relatively insensitive to the rate of atropisomer interconversion compared to the rate of racemate elimination. Simulations of the administration of a single atropisomer or the 50/50 racemate, based on all the possible scenarios of individual atropisomer elimination, showed little difference in plasma exposure to the two atropisomers. Potential differences in plasma exposure to the two atropisomers depend, to a larger extent, on the ratio of the rate of atropisomer interconversion versus racemate elimination and, to a lesser extent, on the conformation of atropisomers administered. When atropisomer interconversion is 10-fold or more rapid than racemate elimination, the largest possible difference in plasma exposure between the two atropisomers is below 20%, regardless of the route and conformation of the atropisomer(s) administered.
Historically, nature has provided the source for the majority of the drugs in use today. More than 20,000 microbial secondary metabolites have been described, but only a small percentage of these have been carried forward as natural product drugs. Natural products are in tough competition with large chemical libraries and with combinatorial chemistries. Hence, each step of a natural product program has to be more efficient than ever, starting from the collection of environmental samples and the selection of strains, to metabolic expression, genetic exploitation, sample preparation and chemical dereplication. This review will focus on approaches for diversifying microbial natural product strains and extract libraries, while decreasing genetic and chemical redundancy.
A model for the solar coronal magnetic field is proposed where multiple directed loops evolve in space and time. Loops injected at small scales are anchored by footpoints of opposite polarity moving randomly on a surface. Nearby footpoints of the same polarity aggregate, and loops can reconnect when they collide. This may trigger a cascade of further reconnection, representing a solar flare. Numerical simulations show that a power law distribution of flare energies emerges, associated with a scale-free network of loops, indicating self-organized criticality.
BACKGROUND: Traditional epidural techniques have been associated with prolonged labour, use of oxytocin augmentation, and increased incidence of instrumental vaginal delivery. The combined spinal-epidural (CSE) technique has been introduced in an attempt to reduce these adverse effects. CSE is believed to improve maternal mobility during labour and provide more rapid onset of analgesia than epidural analgesia. OBJECTIVES: To assess the relative effects of combined spinal-epidural versus epidural analgesia during labour. SEARCH STRATEGY: The Cochrane Pregnancy and Childbirth Group Trials Register (July 2002), the Cochrane Controlled Trials Register (The Cochrane Library, Issue 3, 2002), MEDLINE (1966 to June 2002) and EMBASE (1974 to June 2002). SELECTION CRITERIA: All published randomised controlled trials involving a comparison of CSE with epidural analgesia initiated for women in the first stage of labour. DATA COLLECTION AND ANALYSIS: Trials identified from searching were assessed for inclusion by the same two reviewers independently. Review Manager software was used for calculation of the treatment effect represented by odds ratios (OR) and weighted mean difference (WMD) using a fixed effects model with 95% confidence intervals (CI). MAIN RESULTS: Fourteen trials (2047 women) met our inclusion criteria. Of the 25 outcomes analysed from these studies CSE shows a reduced time from first injection to effective maternal analgesia WMD -5.50 minutes (95% CI -6.47 to -4.52; four trials), an increased incidence of maternal satisfaction OR 4.69 (95% CI 1.27 to 17.29; three trials), and an increased incidence of pruritus OR 2.79 (95% CI 1.87 to 4.18; nine trials). No difference was found between CSE and epidural techniques with regards to maternal mobility, rescue analgesia requirements, the incidence of post dural puncture headache (PDPH) or blood patch, hypotension, urinary retention, mode of delivery, or admission of the baby to the neonatal unit. REVIEWER'S CONCLUSIONS: There is no standard CSE or epidural technique. Compared with epidural, CSE provides faster onset of effective pain relief from the time of injection, and increases the incidence of maternal satisfaction. However, CSE women experience more itch. There is no difference between CSE and epidural techniques with respect to: the incidence of forceps delivery, maternal mobility, PDPH, caesarean section rates or admission of babies to the neonatal unit. It is not possible to draw any meaningful conclusions regarding rare complications such as nerve injury and meningitis.
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BACKGROUND: Sentinel node biopsy affords the opportunity of focused examination of lymph nodes, including the use of the reverse transcriptase-polymerase chain reaction (RT-PCR). The mammaglobin gene is expressed by breast cancers but has not been detected in histologically normal lymph nodes. This study compared mammaglobin RT-PCR with routine histology in the sentinel and non-sentinel nodes of patients with breast cancer. METHODS: Patients with breast cancer underwent tumour excision, sentinel node biopsy and axillary dissection. All nodes were bisected and half of each node was sent for routine histological examination. The other half underwent RNA extraction and mammaglobin RT-PCR. RESULTS: Sentinel node biopsy was successful in 50 (96 per cent) of 52 patients. Mammaglobin expression was detected in nine (8 per cent) of 119 histologically negative sentinel nodes (Clopper-Pearson 95 per cent confidence interval (c.i.) 4 to 14 per cent) and in 13 (5 per cent) of 247 histologically negative non-sentinel nodes (95 per cent c.i. 3 to 9 per cent). Mammaglobin expression was detected in four (13 per cent) of 31 patients with histologically negative sentinel nodes (95 per cent c.i. 4 to 30 per cent) and in six (14 per cent) of 44 patients with histologically negative non-sentinel nodes (95 per cent c.i. 5 to 27 per cent). The false-negative rate for sentinel node biopsy was zero using histology results and 10 per cent using RT-PCR. CONCLUSION: RT-PCR screening of axillary nodes for mammaglobin expression increased the detection of breast cancer metastases compared with routine histology.
BACKGROUND: Non-heart-beating donor (NHBD) livers represent an important organ pool, but are seldom utilized clinically and require rapid retrieval and implantation. Experimental work with oxygenated perfusion during preservation has shown promising results by recovering function in these livers. This study compared sanguinous perfusion with cold storage for extended preservation of the NHBD liver in a porcine model. METHODS: Porcine livers were subjected to 60 min of in vivo total warm ischaemia before flushing, after which they were preserved by one of two methods: group 1 (n = 4), University of Wisconsin (UW) solution by standard cold storage for 24 h; group 2 (n = 4), oxygenated autologous blood perfusion on an extracorporeal circuit for 24 h. All livers were subsequently tested on the circuit during a 24-h reperfusion phase. RESULTS: Livers in group 1 showed no evidence of viability during the reperfusion phase with no bile production or glucose utilization; they also displayed massive necrosis. Livers in group 2 demonstrated recovery of function by synthetic function, substrate utilization and perfusion haemodynamics; these livers displayed less cellular injury by hepatocellular enzymes. All differences in parameters between the two groups were statistically significant (P < 0.05). These findings were supported by histological examination. CONCLUSION: Warm ischaemia for 1 h and simple cold storage (UW solution) for 24 h renders the liver non-viable. Oxygenated, sanguinous perfusion as a method of preservation recovers liver function to a viable level after 24 h of preservation.
A general preparation of pyridines 4a-f from stabilized ketones 3a-c and aryl ketones 3d-f is described. The annulation of stabilized esters 3g,h gives access to the corresponding 2-pyridones 4g,h. The annulation reactions proceed in fair to excellent yields (46-87%) with vinamidinium hexafluorophosphate salts 2a-d containing electron-withdrawing groups at the beta-position. The mechanism of the reaction was investigated by NMR and proceeds through the formation of a dienaminone intermediate.
OBJECTIVE: To determine the incidence of and risk factors for ventilatory failure in dogs undergoing surgery for treatment of cervical spinal disorders and to document ventilator management, clinical course, and long-term outcome of dogs that experienced ventilatory failure in association with cervical spinal disorders or their management. DESIGN: Retrospective study. ANIMALS: 14 dogs. PROCEDURE: Dogs with cervical spinal disorders that required positive-pressure ventilation (PPV) were identified, and signalment, concurrent diseases, neurologic status at initial examination, clinical course, pulmonary function before, during, and after PPV, management techniques, complications, and outcome were recorded. Dogs that underwent surgery and required PPV were compared with dogs that underwent cervical spinal surgery during the same period that did not require PPV. RESULTS: 14 dogs with cervical spinal disorders required PPV to treat hypoventilation, including 13 of 263 (4.9%) dogs that underwent surgery for cervical spinal disorders. Lesions between the second and fourth cervical vertebrae and treatment by means of a dorsal decompressive laminectomy were associated with a significantly increased risk of perioperative hypoventilation. Pulmonary gas exchange function was normal or nearly normal throughout the course of PPV in dogs that survived. Ten dogs survived, and 9 of the 10 regained neurologic function. All 9 dogs that regained neurologic function had deep pain perception on initial examination at the veterinary teaching hospital. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that a small percentage of dogs with cervical spinal disorders may require perioperative ventilatory support. With prolonged PPV and aggressive management, a good outcome may be achieved in dogs similar to those described in the present study.
Substituted acetic acids and formamides react in the presence of phosphorus oxychloride to yield the vinamidinium hexafluorophosphate salts 5a-d, 6a-d, and 7 in moderate to good unoptimized recrystallized yields (40-67%) as easily handled nonhygroscopic solids. The 1,3-differentially substituted vinamidinium salts 8 was prepared by amine exchange in 81% yield as are the cyclic diazapinium salts 9 and 10 in > 76% yield. The symmetrical 2-chlorovinamidinium 11 was prepared by displacement of 3 in 71% yield. The 2-chlorovinamidinium salts are cleanly reduced to the parent vinamidinium salts 12-16 using HI or PPh3/pTSA in up to 99% assay yield.
OBJECTIVES: To assess the contraceptive efficacy, tolerability and acceptability of hormonally impregnated intrauterine systems (IUSs) in comparison to other reversible contraceptive methods. SEARCH STRATEGY: Literature was identified through database searches, reference lists and individuals/organisations working in the field. SELECTION CRITERIA: All randomised controlled trials comparing IUSs with other forms of reversible contraceptives and reporting on pre-determined outcomes in women of reproductive years. The primary outcomes were pregnancy due to method/user failure and continuation rate. DATA COLLECTION AND ANALYSIS: The quality assessment of studies and data extraction were completed independently by two blinded reviewers. A quality checklist was designed to identify general methodological and contraceptive specific factors which could bias results. Events per women months and single decrement life table rates were extracted where possible for pregnancy, continuation, adverse events and reasons for discontinuation. Events per total number of women at follow up were collected for hormonal side effects and menstrual disturbance. When appropriate, data were pooled at the same points of follow up to calculate rate ratios in order to determine the relative effectiveness of one method compared to another. For the single decrement life table rates, the rate differences were pooled to determine the absolute difference in effectiveness of one method compared to another. Interventions were only combined if the contraceptive methods were similar. Non-hormonal IUDs were divided into three categories for the purpose of comparison with IUSs: IUDs >250mm2 (i.e. CuT 380A IUD and CuT 380 Ag IUD), IUDs <=250mm2 (i.e. Nova-T, Multiload, CuT 200 and CuT 220 IUDs) and non-medicated IUDs. MAIN RESULTS: Nineteen RCTs comparing hormonally impregnated IUSs to a reversible contraceptive method met the inclusion criteria and it was possible to include eight of these in the meta-analyses, four comparing LNG-20 IUSs with non-hormonal IUDs, one comparing the LNG-20 IUS with Norplant-2 and three comparing Progestasert with non-hormonal IUDs. No significant difference was observed between the pregnancy rates for the LNG-20 users and those for the IUD >250mm2 users. However, women using the LNG-20 IUS were significantly less likely to become pregnant than those using the IUD <=250mm2. Women using the LNG-20 IUS were more likely to experience amenorrhoea and device expulsion than women using IUDs >250mm2. LNG-20 users were significantly more likely than all the IUD users to discontinue because of hormonal side effects and menstrual disturbance, which on further breakdown of the data was due to amenorrhoea. When the LNG-20 IUS was compared to Norplant-2, the LNG-20 users were significantly more likely to experience amenorrhoea and oligomenorrhoea, but significantly less likely to experience prolonged bleeding and spotting. No other significant differences were observed. Progestasert users were significantly less likely to become pregnant and less likely to continue on the method than non-medicated IUD users after one year, but no significant differences was noted for these two outcomes when Progestasert users were compared to IUD<=250mm2 users. The only other significant differences found in the meta-analyses were that Progestasert users were less likely to expel the device and more likely to discontinue the method because of menstrual bleeding and pain than users of IUDs <=250mm2. REVIEWER'S CONCLUSIONS: Current evidence suggests LNG-20 IUS users are no more or less likely to have unwanted pregnancies than IUD >250mm2 and Norplant-2 users. The LNG-20 IUS was more effective in preventing either intrauterine or extrauterine pregnancies than IUDs <=250mm2. The contraceptive effectiveness of Progestasert was significantly better than non-medicated IUDs, but no difference was observed when compared to IUDs<=250mm2. Continuation of LNG-20 IUS use was similar to continuation of the non-hormonal IUDs and Norplant-2. Amenorrhoea was the main reason for the discontinuation for the LNG-20 IUS and women should be informed of this prior to starting this method.
The development of transgenic mouse models of amyotrophic lateral sclerosis (ALS) allows the testing of neuroprotective agents. We evaluated the effects of five agents in transgenic mice with the G93A Cu,Zn superoxide dismutase mutation. A novel inhibitor of poly(ADP-ribose) polymerase showed no effects on survival. Desmethylselegiline and CGP3466 are agents that exert antiapoptotic effects in vitro by preventing nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase. They had no significant effects on survival in the G93A mice. Trientine, a copper chelator, produced a modest significant increase in survival. Similarly administration of lipoic acid in the diet produced a significant improvement in survival. These results therefore provide evidence for potential therapeutic effects of copper chelators and lipoic acid in the treatment of ALS.
Giant lymph node hyperplasia (GLNH) or Castleman's disease is a rare pathological entity commonly presenting as a solitary mediastinal tumour (unifocal variant), although other anatomical sites have been reported including the head and neck, abdomen and axilla. Though the head and neck is the second commonest site for this lesion, only 60 cases [1,2] have been reported in the literature. Pre-operative diagnosis of the unifocal variant can be difficult as routine investigations carried out in the clinic setting are often inconclusive. A multicentric form of this disease with a poorer prognosis in comparison to the unifocal lesion has been described by Gaba et al. in 1978 [3]. We present a case of an unusually large, slow growing, asymptomatic, unifocal variant of this tumour restricted to the neck which underwent successful surgical excision. A review of the literature, histopathological characteristics and differential diagnosis is also presented.
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AIMS: To identify and compare doctors' and nurses' perceptions of ethical problems. Rationale. Ethical problems are a source of tension for health professionals. Misunderstandings or conflicts may result from differing perceptions of ethical problems. If true collaboration is to be achieved, it is important to understand the perspectives of others, particularly when difficult end-of-life decisions must be made. METHODS: In this qualitative study a total of seven doctors and 14 nurses working in acute care adult medical-surgical areas, including intensive care, were asked to describe ethical problems that they frequently encounter in practice. Interviews were taped and transcribed. Thematic analysis followed. RESULTS: All participants experienced ethical problems around decision making at the end of life. The core problem for both doctors and nurses was witnessing suffering, which engendered a moral obligation to reduce that suffering. Uncertainty about the best course of action for the patient and family was a source of moral distress. Competing values, hierarchical processes, scarce resources, and communication emerged as common themes. The key difference between the groups was that doctors are responsible for making decisions and nurses must live with these decisions. Each group, therefore, asked different questions when encountering and interpreting sources of moral distress. CONCLUSIONS: It was concluded that observed differences between doctors and nurses were a function of the professional role played by each rather than differences in ethical reasoning or moral motivation. Although this was a small qualitative study on one institution, and may not be generalizable, results suggest that doctors and nurses need to engage in moral discourse to understand and support the ethical burden carried by the other. Administrators should provide opportunities for discourse to help staff reduce moral distress and generate creative strategies for dealing with this.
Fusidic acid resistance resulting from mutations in elongation factor G (EF-G) of Staphylococcus aureus is associated with fitness costs during growth in vivo and in vitro. In both environments, these costs can be partly or fully compensated by the acquisition of secondary intragenic mutations. Among clinical isolates of S. aureus, fusidic acid-resistant strains have been identified that carry multiple mutations in EF-G at positions similar to those shown experimentally to cause resistance and fitness compensation. This observation suggests that fitness-compensatory mutations may be an important aspect of the evolution of antibiotic resistance in the clinical environment, and may contribute to a stabilization of the resistant bacteria present in a bacterial population.