Biomedical subjects
R Thomas
Publications and source records attributed to R Thomas.
Thrombin inhibitors based on [5,5] trans-fused indane lactams.
A series of trans-fused lactams containing the indane nucleus has been prepared. Compound 19 has much enhanced plasma stability compared with its lactone counterpart and shows appreciable in vitro anticoagulant activity.
Azide as a competitor of chloride in oxygen evolution by Photosystem II.
Oxygen evolution by higher plants requires chloride, which binds to a site associated with the oxygen-evolving complex of photosystem II (PSII). In this study, the inhibitory effect of the anion azide was characterized using steady state measurements of oxygen evolution activity in PSII-enriched thylakoid membranes. N3- (7.8 mM) inhibited O2 evolution activity by 50% when a standard buffer containing chloride was used. By considering Cl- as the substrate in O2 evolution assays, we found azide to be primarily competitive with Cl- with an inhibitor dissociation constant Ki of about 0.6 mM. An uncompetitive component with a Ki ' of 11 mM was also found. Removal of the 17 and 23 kDa polypeptides resulted in a decrease in each inhibition constant. A pH dependence study of O2 evolution activity showed that the pH maximum became narrower and shifted to a higher pH in the presence of azide. Analysis of the data indicated that an acidic residue defined the low side of the pH maximum with an apparent pKa of 6.7 in the presence of azide compared with 5.5 for the control. A basic residue was also affected, exhibiting an apparent pKa of 7.1 compared with a value of 7.6 for the control. This result can be explained by a simple model in which azide binding to the chloride site moves negative charge of the anion away from the basic residue and toward the acidic residue relative to chloride. As a competitor of chloride, azide may provide an interesting probe of the oxygen-evolving complex in future studies.
Nursing home placement is related to dementia progression: experience from a clinical trial. Alzheimer's Disease Cooperative Study.
OBJECTIVES: To examine the relationship between nursing home placement (NHP) and measures of change in other well-established clinical disease assessments in a longitudinal study of patients with probable AD. BACKGROUND: NHP is a common, major milestone in the natural history of AD. NHP is a readily identified event that can be accurately dated. NHP can be used in survival analyses, which are an efficient means of determining efficacy in clinical trials. NHP usually occurs in the setting of severe AD, but in cross-sectional studies, the strength of the association with disease severity has been controversial. DESIGN/METHODS: We used data from 341 AD patients who were enrolled in a recently published clinical trial of selegiline and tocopherol. At entry, all were rated as Clinical Dementia Rating (CDR) stage 2, were community-dwelling, and had an identified caregiver. Patients were followed at 3-month intervals for 2 years. We examined the relationship between four measures of dementia severity and a measure of behavioral dysfunction and NHP. The measures included changes in CDR status, changes in activities of daily living performance, changes from baseline to last measurement in dependence level, changes from baseline to last measurement on the Blessed Dementia Rating Scale (BDRS) score, and changes from baseline to last measurement on the total score and subscales of the Behavior Rating Scale for Dementia (BRSD). Statistical models were used to assess the strength of the associations. RESULTS: At the end of the 2-year period, 33% of patients had been institutionalized. The NHP patients did not differ at baseline from the not-NHP patients in gender, age, caregiver status, duration of illness, CDR sum of boxes, BDRS, or dependence level. The NHP patients had a lower baseline Mini-Mental State Examination score and a slightly worse BRSD total score. Patients reaching CDR3 were eight times more likely to be institutionalized than those who remained at CDR2. The change scores on all four dementia severity measures were strongly associated with NHP; the change score on the BRSD and its subscales were not. On the other hand, adverse events that included a behavioral disturbance, especially agitation, were associated with NHP. CONCLUSION: These data show that NHP closely reflects dementia progression in the context of a clinical trial. Coupled with the high face validity of NHP as a milestone of severe dementia, NHP is a valid primary outcome measure for AD clinical trials.
Rapid thinning of parts of the southern greenland ice sheet
Aircraft laser-altimeter surveys over southern Greenland in 1993 and 1998 show three areas of thickening by more than 10 centimeters per year in the southern part of the region and large areas of thinning, particularly in the east. Above 2000 meters elevation the ice sheet is in balance but thinning predominates at lower elevations, with rates exceeding 1 meter per year on east coast outlet glaciers. These high thinning rates occur at different latitudes and at elevations up to 1500 meters, which suggests that they are caused by increased rates of creep thinning rather than by excessive melting. Taken as a whole, the surveyed region is in negative balance.
Evidence based patient information. Local policies would be better than a national strategy.
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Neurochemical markers do not correlate with cognitive decline in the Lewy body variant of Alzheimer disease.
BACKGROUND: Reductions in neocortical synapses and cholinergic function occur in patients with Alzheimer disease (AD) and in patients with the Lewy body variant of AD (LBV). The relation between these losses and cognitive decline has been reported frequently in patients with AD but remains unclear for patients with LBV. OBJECTIVES: To investigate the relation between clinical markers of disease progression and choline acetyltransferase activity or synaptic density, measured by synaptophysin (Syn) level, in patients with LBV, and to investigate the relation of these neurochemical markers with one another. METHODS: Brain specimens of 41 patients with autopsy-confirmed (National Institute on Aging criteria for AD) LBV were examined. The last Mini-Mental State Examination and Blessed Information-Memory-Concentration test scores before death were reviewed. Midfrontal synapse counts were quantified by a dot-immunobinding assay for Syn. Choline acetyltransferase activity of the midfrontal cortex was assayed by established protocols. RESULTS: The last Mini-Mental State Examination score before death did not correlate significantly with Syn level (n = 25, r = 0.25, P = .24); however, there was a trend toward significance for the relation between last Mini-Mental State Examination score and choline acetyltransferase activity (n = 39, r = 0.31, P = .05). The last Blessed Information-Memory-Concentration test score did not correlate with either Syn level (n = 24, r = -0.17, P = .44) or choline acetyltransferase activity (n = 39, r = -0.16, P = .33). Finally, there was only a modest correlation between Syn level and choline acetyltransferase activity (n = 25, r = 0.38, P = .06), which did not reach statistical significance. CONCLUSION: Unlike AD, neurochemical markers do not appear to correlate well with cognitive decline in LBV.
Corneal thickness in ocular hypertension, primary open-angle glaucoma, and normal tension glaucoma.
OBJECTIVES: To determine the effect of central corneal thickness (CCT) on the measurement of intraocular pressure (IOP) and on the resultant reclassification of patients as having primary open-angle glaucoma (POAG), normal tension glaucoma (NTG), or ocular hypertension (OHT). METHODS: Intraocular pressure (Goldmann applanation tonomety) and CCT (ultrasound pachymetry) were measured in 22 patients with NTG, 49 with POAG, 44 with OHT and in 18 control subjects. The CCT was used to obtain a corrected value for the IOP and to reclassify the type of glaucoma. RESULTS: There was no significant difference in CCT between controls (552 +/- 35 microns) and patients with POAG (543 +/- 35 microns), but the CCT in the group with NTG (521 +/- 31 microns) was significantly lower than that in the control group or the group with POAG (P < .001), and the CCT in the group with OHT (583 +/- 34 microns) was significantly higher than in controls or patients with POAG (P < .001). Correcting IOP for corneal thickness, 31% of the patients with NTG could be reclassified as having POAG, and 56% of the patients with OHT as normal. CONCLUSIONS: Patients with NTG have a thinner CCT than do patients with POAG or controls. Underestimation of the IOP in patients with POAG who have thin corneas may lead to a misdiagnosis of NTG, while overestimation of the IOP in normal subjects who have thick corneas may lead to a misdiagnosis of OHT.
Dendritic cells and the pathogenesis of rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease in which unknown arthrogenic autoantigen is presented to CD4+ T cells. The strong association of the disease with an epitope within the HLA-DR chain shared between various alleles of HLA-DR4 and DR1 emphasizes the importance of antigen presentation. This immune response predominantly occurs in the synovial tissue and fluid of the joints and autoreactive T cells are readily demonstrable in both the synovial compartment and blood. Circulating dendritic cells (DC) are phenotypically and functionally identical with normal peripheral blood (PB) DC. In the synovial tissue, fully differentiated perivascular DC are found in close association with T cells and with B cell follicles, sometimes containing follicular DC. These perivascular DC migrate across the activated endothelium from blood and receive differentiative signals within the joint from monocyte-derived cytokines and CD40-ligand+ T cells. In the SF, DC manifest an intermediate phenotype, similar to that of monocyte-derived DC in vitro. Like a delayed-type hypersensitivity response, the rheumatoid synovium represents an effector site. DC at many effector sites have a characteristic pattern of infiltration and differentiation. It is important to note that the effector response is not self-limiting in RA autoimmune inflammation. In this article, we argue that the presentation of self-antigen by DC and by autoantibody-producing B cells is critical for the perpetuation of the autoimmune response. Permanently arresting this ongoing immune response with either pharmaceutical agents or immunotherapy is a major challenge for immunology.
Evaluating supervised HAART in late-stage HIV among drug users: a preliminary report.
OBJECTIVE: To examine response to highly active antiretroviral therapy (HAART) among a sample of treatment-experienced patients in the late stage of human immunodeficiency virus (HIV) infection in residential health care facilities (RHCFs) in New York City facilities designated for HIV/AIDS (acquired immunodeficiency syndrome) when access and adherence are maximized. METHODS: Medical record review of 111 patients. RESULTS: Demographics were mean age 42 years; 58% male; 60% African-American; 31% Hispanic; 57% injection drug users (IDUs); 23% with history of dementia; 52% hepatitis C virus (HCV) antibody seropositive; 80% on HAART, of whom 18% had lipodystrophy. Of 88 patients on HAART, 52% had a decreased viral load (>1/2 log) versus 13% of 23 not on HAART (P<.05); a >1/2 log viral load increase was seen in 8% and 35%, respectively (P<.05). Those with viral load increase were more likely than those with stable/decreased viral load to be IDUs (71% vs. 64%) and to have HCV seropositivity (86% vs. 53%), even with similar initial CD4+ cell count, viral load, and follow-up time. CONCLUSION: In a predominantly minority IDU population who are treatment experienced, 50% of the patients successfully responded to treatment with supervised therapy. The RHCFs in New York City provide a unique opportunity to examine further factors associated with response to HAART in an environment in which medication administration and adherence are maximized and monitored carefully.
Trial of dexamethasone treatment for severe bacterial meningitis in adults. Adult Meningitis Steroid Group.
OBJECTIVE: To evaluate the clinical benefit of early adjunctive dexamethasone therapy for severe bacterial meningitis in adults. DESIGN: Multicenter, double-blind, randomized trial initiated in emergency or intensive care units in France and Switzerland. Within 3 h after initiation of an aminopenicillin therapy, patients received dexamethasone (10 mg q.i.d.) or placebo for 3 days. The primary end-point was the rate of patients cured without any neurologic sequelae on day 30. RESULTS: Sixty patients were enrolled, predominantly with a severe form since 85% required ICU stay and 43% mechanical ventilation. Streptococcus pneumoniae accounted for 31 cases and Neisseria meningitidis for 18 cases. The study had to be stopped prematurely because of a new national recommendation of experts to use third generation cephalosporin and vancomycin as a result of the increasing rate of penicillin-resistant S. pneumoniae in France. After the third sequential analysis by the triangular statistical test, the difference of rate of cured patients without any neurologic sequelae was not statistically significant (p = 0.0711) between the dexamethasone group (74.2%; n = 31) and the placebo group (51.7%; n = 29). Furthermore, the former group was younger and less sick at inclusion. CONCLUSION: Bacterial meningitis is still a severe disease in adults, since the overall observed rate of death or severe neurologic sequelae was 26.7%. The reported data are inconclusive regarding a systematic use of dexamethasone as an adjunctive therapy for bacterial meningitis in adults. Moreover this treatment impairs antibiotic penetration into the cerebrospinal fluid (CSF) that can lead to therapeutic failure, particularly in areas with high or increasing rates of penicillin-resistant S. pneumoniae.
Human rabies despite postexposure vaccination.
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1998 American Urological Association Gallup Survey: changes in physician practice patterns, treatment of ureteral stones and impact of managed care.
PURPOSE: The American Urological Association first commissioned the Gallup Organization to conduct a study to assess urologist practice patterns in 1992. We present the results of the seventh consecutive Gallup Survey performed for the Association. MATERIALS AND METHODS: A random sample of 537 American urologists who completed urological residency and practiced at least 20 hours weekly in 1997 were interviewed by telephone in March 1998. Major topic areas included general demographics, practice patterns, treatment of ureteral stones and experience with managed care. RESULTS: Demographic trends indicated a significant decrease in average urologist age from 49.4 years in 1992 to 46.8 in 1998. Of the urologists 99% reported that they treat ureteral stones. Managed care had an increasingly larger role in most practices, particularly in the western United States, where 73% of urologists reported that they contract with a Medicare health maintenance organization. CONCLUSIONS: The average age of practicing urologists significantly decreased, which may be due to an increasing number of urologists retiring at an earlier age, although this finding is not clear. Nearly all urologists treated ureteral stones with considerable consistency. Finally, managed care appeared to have a major impact on most urologists throughout the United States.
Incidence of immediate and delayed hypersensitivity to Centruroides antivenom.
STUDY OBJECTIVE: To assess the incidence and course of immediate and delayed hypersensitivity to Centruroides antivenom. METHODS: We performed a 12-month prospective observation study, with telephone follow-up, evaluating the incidence of anaphylaxis or anaphylactoid reactions and serum sickness after Centruroides antivenom administration. The setting for the study was a poison control center and tertiary care toxicology treatment center. Participants included all patients who received Centruroides antivenom, and no interventions were performed. RESULTS: For immediate hypersensitivity reactions, 116 patients with grade III or IV envenomation received Centruroides antivenom; 77 of these patients were younger than 13 years. Three patients completed the infusion despite development of rash. A fourth patient with a history of atopy and asthma received epinephrine infusion and an inhaled beta-agonist for transient wheezing that quickly resolved; she was admitted for observation. Nine patients without hypersensitivity reactions were admitted for social reasons, for inappropriate sedation from drugs used before antivenom, or to rule out aspiration; all were discharged within 24 hours. The remaining 106 patients were discharged from the emergency department after resolution of symptoms. Thus 4 of 116 patients had immediate reactions. For patients with delayed reactions, 17 patients were lost to follow-up. Of 99 remaining patients, serum sickness developed in 61% (n=60), as defined by using liberal criteria. Serum sickness responded to oral steroids, antihistamines, or both; mean duration of symptoms with medication was 2.8 days. CONCLUSION: Anaphylactic reactions are uncommon after Centruroides antivenom infusion. Self-limited serum sickness that is easily controlled with corticosteroids and antihistamines commonly follows the use of Centruroides antivenom.
Cisplatin-epirubicin-paclitaxel weekly administration in advanced breast cancer: a phase I study of the Southern Italy Cooperative Oncology Group.
PURPOSE: Both cisplatin and epirubicin have been shown to enhance the antitumor activity of paclitaxel in vitro. Weekly administration could result in a substantial improvement in the therapeutic index of cisplatin and paclitaxel. This study was aimed at determining the MTDs of epirubicin and paclitaxel given weekly with a fixed dose of cisplatin. PATIENTS AND METHODS: Sixty-three breast cancer patients with advanced disease (24 locally advanced and 39 metastatic), who had not received prior chemotherapy (except adjuvant), received weekly cisplatin (CDDP) doses of 30 mg/m2 together with escalating doses of paclitaxel (PTX) and epirubicin (EPI) for a minimum of six cycles. The dose escalation was stopped if DLT occurred during the first six treatment cycles in > 33% of patients of a given cohort. RESULTS: Nine different dose levels were tested, for a total of 506 weekly cycles delivered. G-CSF support on days 3-5 of each week was also given in the last four cohorts (24 patients). An overall 11 patients showed DLT in the first six cycles. EPI and PTX doses up to 40 and 85 mg/m2/week, respectively, were safely delivered without G-CSF support. However, the actually delivered mean dose intensity was only 64% in this cohort. Therefore, the dose escalation continued with the addition of filgrastim from day 3 to day 5 each week. Doses of EPI and PTX up to 50 and 120 mg/m2/week were administered without observing DLT in the first six cycles in more than one third of the patients enrolled. No toxic deaths were observed. Only two patients had to be hospitalized because of sepsis. Grade 3-4 neutropenia, thrombocytopenia, and anemia occurred in 25, 9, and 16 patients, respectively. Alopecia was almost universal. Other nonhematologic toxicities were generally mild, being of grade 3-4 in only eight patients (fatigue and loss of appetite in two cases, diarrhoea in four cases, peripheral neuropathy and mucositis in one case). Fifteen complete and 37 partial responses have been registered for an 82% (95% CI = 71-91) overall clinical response rate (ORR). Eight complete and 14 partial responses occurred in the 24 patients with locally advanced disease, for a 92% (95% CI = 73-99) ORR, as compared to seven complete and 23 partial responses in the 39 women with metastatic disease, 77% (95% CI = 61-89). A clear dose-response relationship was not observed, since an overall response rate of at least 70% was achieved at all dose levels. However, the ORR increased to 92% in the last four cohorts which included patients who received higher doses of EPI and PTX with G-CSF support. All of the 24 patients with locally advanced disease underwent modified radical mastectomy with axillary dissection. Three of them showed no invasive cancer on pathologic examination, and in another five patients a tumor smaller than 1 cm was found in the surgical specimen of the breast. At a nine-month median follow-up (range 2-14), 11 patients have progressed and three have died. Twenty-three out of 24 patients who underwent surgery are still free from progression. The one-year projected progression-free survival is 77% for the whole population. CONCLUSIONS: The CDDP/EPI/PTX weekly administration is a well tolerated and very effective approach in advanced breast cancer patients. Full doses of all the three drugs can be delivered even in absence of G-CSF support. A very impressive increment of the dose-intensity can be obtained, however, by adding filgrastim. A phase II study is under way to better define the therapeutic efficacy of this regimen in patients with advanced breast cancer.
Patients' preferences for video cassette recorded information: effect of age, sex and ethnic group.
The emotional turmoil patients endure following a diagnosis of cancer can impair their ability to retain complex treatment-related information. Manoeuvres which increase the intensity of information have been shown to increase the amount retained. Providing details of treatment in a video format is one method of intensifying information provision, but the attitudes of patients to this format have not previously been evaluated. In this pilot study, the attitudes of 300 patients to video directed information were evaluated via questionnaires, of which 210 (70%) were returned. Eighty-nine per cent had easy access to a video cassette player. A highly significant number felt that the video would be very helpful or helpful (78%) compared to not helpful, worrying or equivocal 21% (P < 0.0001). This trend was particularly strong in patients < 60 years (83% versus 17%) (P < 0.0001) and those from ethnic groups (95% versus 5%) (P < 0.0001). As a result of this trial, a 20-min film (HEP) has been commissioned. It describes details of the two main treatments for cancer after surgery, namely chemotherapy and radiotherapy, shows patients actually having treatment, and explains the common side-effects and ways to alleviate them. Patients satisfaction with the film and its effect on anxiety and depression are currently being evaluated in an international prospective randomized trial. If it proves advantageous for patients--in view of the ethnic group bias in this study--it will be translated into the ethnic languages of the UK.
Dendritic cells: the driving force behind autoimmunity in rheumatoid arthritis?
Dendritic cells (DC) are likely to play a significant role in immune-mediated diseases such as autoimmunity and allergy. To date there are few treatments capable of inducing permanent remission in rheumatoid arthritis (RA) and elucidation of the role of DC may provide specific strategies for disease intervention. Dendritic cells have proven to be powerful tools for immunotherapy and investigations are under way to determine their clinical efficacy in transplantation and viral and tumour immunotherapy. The present review will focus on the current view of DC and their role in autoimmunity, in particular RA. Two possible roles for DC in the pathogenesis of RA will be proposed, based on recent advances in the field.
Patient information materials in oncology: are they needed and do they work?
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