Sequential parathyroid hormone/alendronate therapy for osteoporosis--robbing Peter to pay Paul?
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Adult↗
Biomedical subjects
A Stewart
Publications and source records attributed to A Stewart.
Quantitative ultrasound or clinical risk factors--which best identifies women at risk of osteoporosis?
Dual energy X-ray absorptiometry (DXA) is the current technique of choice to assess risk of future fracture and to diagnose osteoporosis as defined by bone mineral density (BMD). Guidelines for bone densitometry referral have been published listing clinical risk factors that might be considered grounds for assessment. However, these factors are known to be poorly predictive of subsequent BMD measurement and, accordingly, new inexpensive methods of selecting subjects for assessment should be sought. Quantitative ultrasound (QUS) of bone may be such a technique. Women (n = 250) considered by their general practitioners to be at risk of osteoporosis and who had been referred for DXA measurements of the spine and hip were recruited into the study. All underwent a QUS scan of the heel using a McCue CUBA Clinical machine, which measures broadband ultrasound attenuation (BUA) and velocity of sound (VOS), a clinical risk factor questionnaire, and spine and hip BMD measurement by a Norland XR-26 bone densitometer. Patients were categorized according to published diagnostic criteria for BMD, and these were also applied to the QUS parameters. Risk factors were arbitrarily categorized into "low", "medium" and "high" risk groups. Kappa scores were calculated to analyse the agreement between different techniques. Receiver operator characteristic (ROC) analyses were undertaken to demonstrate the technique with the best sensitivity and specificity for the detection of low BMD at the spine and hip. Analysis of the bone mass data demonstrated only moderate agreement (kappa 0.33) between femoral neck and spine BMD with femoral neck BMD and BUA showing a very similar level of agreement (kappa 0.31). ROC analysis demonstrated that VOS followed by BUA was the best predictor of low BMD, with risk factors alone being significantly poorer; QUS parameters are better predictors than clinical risk factors for women with low BMD and could be used effectively at the primary care level to indicate those who should be considered for full osteoporosis assessment. However, further study into the cost effectiveness of this approach is required.
Absorptiometry, Photon↗
The role of epidemiology in the detection of harmful effects of radiation.
Data relating to acute injuries of atomic bomb survivors show that the life span study cohort is biased in favor of exceptionally low levels of radiosensitivity. These data also show that factors influencing the death rates of this cohort include irreversible damage to the immune system. These impressions are still awaiting confirmation. Meanwhile, the Oxford Survey of Childhood Cancers and surveys of nuclear workers show that at low dose levels the cancer risk is much greater than estimates based on atomic bomb survivors; the special association between leukemia and radiation is an exclusively high dose effect, and levels of radiosensitivity are much lower in the middle of the life span than at either extreme.
Cohort Studies↗
Local and systemic effects of intra-arterial desmopressin in healthy volunteers and patients with type 3 von Willebrand disease. Role of interleukin-6.
Intra-arterial desmopressin caused dose and time dependent increases (p <0.001 for all) in forearm blood flow (all doses) and plasma tissue plasminogen activator (t-PA) concentrations (desmopressin > or = 70 ng/min). Although plasma t-PA concentrations rose in both forearms, there was a modest local release of t-PA in the infused forearm (14 ng/100 mL of tissue/min, p <0.05). At desmopressin doses > or = 300 ng/min, plasma von Willebrand factor (vWf) and Factor VIII:C concentrations rose in both forearms (p <0.001) and correlated with the rise in interleukin-6 concentrations (r = 0.92, p <0.001: r = 0.85, p = 0.002 respectively). Neither desmopressin nor substance P caused t-PA, vWf or Factor VIII:C release in the patients, although desmopressin increased plasma interleukin-6 concentrations as in healthy volunteers. We conclude that desmopressin releases t-PA, vWf and Factor VIII:C predominantly via systemic mechanisms, possibly mediated by cytokine release. Patients with type 3 vWD appear to have a generalised failure to release t-PA acutely despite a normal interleukin-6 response to desmopressin infusion.
Adult↗
Phase I trial of XR9576 in healthy volunteers demonstrates modulation of P-glycoprotein in CD56+ lymphocytes after oral and intravenous administration.
XR9576 is a novel inhibitor of P-glycoprotein (P-gp) that has been shown to reverse P-gp-dependent multidrug-resistance in tumor cell lines and tumor-bearing animals. Here we report the first i.v. and p.o. administration to healthy volunteers of XR9576 in dose-escalating studies with the aim of investigating its effects on safety, its pharmacokinetics, and a surrogate marker of efficacy. XR9576 was administered as a single dose-upward titration of 0.1, 0.2, 0.5, 1.0, and 2 mg/kg XR9576 i.v. or 50, 100, 200, 500, and 750 mg/volunteer p.o. The surrogate marker for in vivo efficacy examined the accumulation of the P-gp substrate Rhodamine-123 (Rh-123) in P-gp-expressing CD56+ lymphocytes by flow cytometry. Addition of Rh-123 to blood samples from subjects given XR9576 or a placebo demonstrated drug-dependent modulation of P-gp activity. Even at the lowest doses, significant effects were observed on Rh-123 accumulation in CD56+ cells. Maximal effects were seen during the i.v. infusion or 4-6 h after oral administration. As the dose was increased, a concomitant rise in the level and duration of P-gp blockade was observed. A dose of 2.0 mg/kg i.v. and > or = 200 mg/volunteer p.o. gave approximately 100% inhibition of P-gp for in excess of 24 h. All doses of XR9576 were well tolerated. Inhibition increased with XR9576 plasma concentration, and maximal activity was achieved at 150-200 ng/ml XR9576. In conclusion, XR9576 has demonstrated sustained inhibition of P-gp after i.v. and oral administration and, supported by the elimination half-life of about 24 h, XR9576 is being taken into Phase II as a once-daily agent.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Creating your own medical Internet library.
Many physicians struggle to keep up with new developments in their fields. The internet can provide a solution to this problem by allowing rapid access to a broad spectrum of reliable information. Becoming familiar with a few clinically relevant and freely available medical resources on the World Wide Web may enhance a physician's efforts to provide evidence-based care on a daily basis. This article outlines a simple strategy for physicians to make the internet a useful tool.
Databases, Bibliographic↗
Supercritical fluid chromatography in forensic science: a critical appraisal.
The application of supercritical fluid chromatography (SFC) in forensic science is reviewed. The applications centre on the analysis of explosives and of drugs of abuse. The systems employed are discussed in the context of comparison with gas chromatography and high-performance liquid chromatography methods which are traditionally used for such analyses. The advantages and disadvantages of SFC over these methods are discussed. Recommendations are made for the developments which are required in SFC technology if it is to find greater application in forensic science.
Chromatography, High Pressure Liquid↗
Cervical and trochanteric hip fractures: bone mass and other parameters.
We examined 310 hip fracture patients (55 men, 255 women) to identify differences in those patients who had suffered a cervical fracture compared with those with a trochanteric fracture of the hip. Patients underwent a dual-energy X-ray absorptiometry (DXA) scan of their hip and total body and quantitative ultrasound (QUS) scans of their heel. Other measurements included medical/drug history. Significant differences were found for broadband ultrasound attenuation (BUA) and DXA total-body measurements, with those with a cervical fracture having a higher bone mass. Those with a trochanteric fracture showed a significantly higher incidence of stroke (12.8% vs. 6.3%, p = 0.05), while high blood pressure/antihypertensive therapy was significantly more common in the cervical fracture group (11.6% vs. 4.3%, p < 0.03). Therefore, it is not only bone parameters that differ in these patients. In the presence of certain medical conditions, preventative therapy may be directed to managing co-existing conditions as well as improving bone density.
Absorptiometry, Photon↗
Economics and cost-effectiveness in evaluating the value of cardiovascular therapies. A survey of standards and guidelines for cost-effectiveness analysis in health care.
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Cardiovascular Agents↗
Worldwide variations in the prevalence of symptoms of atopic eczema in the International Study of Asthma and Allergies in Childhood.
BACKGROUND: Little is known about the prevalence of atopic eczema outside Northern Europe. OBJECTIVES: We sought to describe the magnitude and variation in the prevalence of atopic eczema symptoms throughout the world. METHODS: A cross-sectional questionnaire survey was conducted on random samples of schoolchildren aged 6 to 7 years and 13 to 14 years from centers in 56 countries throughout the world. Those children with a positive response to being questioned about the presence of an itchy relapsing skin rash in the last 12 months that had affected their skin creases were considered to have atopic eczema. Children whose atopic eczema symptoms resulted in sleep disturbance for 1 or more nights per week were considered to have severe atopic eczema. RESULTS: Complete data was available for 256,410 children aged 6 to 7 years in 90 centers and 458,623 children aged 13 to 14 years in 153 centers. The prevalence range for symptoms of atopic eczema was from less than 2% in Iran to over 16% in Japan and Sweden in the 6 to 7 year age range and less than 1% in Albania to over 17% in Nigeria for the 13 to 14 year age range. Higher prevalences of atopic eczema symptoms were reported in Australasia and Northern Europe, and lower prevalences were reported in Eastern and Central Europe and Asia. Similar patterns were seen for symptoms of severe atopic eczema. CONCLUSIONS: Atopic eczema is a common health problem for children and adolescents throughout the world. Symptoms of atopic eczema exhibit wide variations in prevalence both within and between countries inhabited by similar ethnic groups, suggesting that environmental factors may be critical in determining disease expression. Studies that include objective skin examinations are required to confirm these findings.
Adolescent↗
Predicting a second hip fracture.
In an attempt to identify a high-risk cohort of patients, who could be offered preventive therapy, we assessed patients who had suffered one hip fracture. A total of 394 patients were prospectively followed to determine those who had suffered a second fracture. Entry bone mass of the unfractured hip and total body was examined by dual X-ray absorptiometry (DXA) and of the os calcis, by quantitative ultrasound (QUS), along with various clinical parameters. The relative risks in the QUS parameters did not reach significance, except for broadband ultrasound attentuation as measured by the McCue CUBA Clinical, whereas femoral neck and total body bone mineral density also reached significance. Lowest quartile body weight was also a significant risk factor as were occurrence of a new fall and poor mobility score. Using Receiver Operator Characteristic curves, we found no significant differences between DXA trochanter or for the Mini Mental State Examination score in predicting those who sustained a second hip fracture. In this elderly group risk factors are almost as good as bone mass at predicting those who will sustain a second hip fracture. Low body weight and poor mobility could be used as triggers for the use of preventive therapy without the use of bone mass measurements and to target expensive preventive therapy to reduce fracture risk.
Absorptiometry, Photon↗
Identification of an HLA-A11 serological variant and its characterization by sequencing based typing.
We have identified an HLA-A11 variant allele, A*1105, segregating in a Caucasoid family. The variant antigen expressed by this allele failed to cross-react with most Caucasoid anti-HLA-A11 antisera tested. Sequencing based typing has been used to characterize this new allele and this showed that it has a novel mutation at a polymorphic position (502) in exon 3. In comparison with A*1101, the mutation (A-->G) results in an amino acid change from positively-charged lysine to negative glutamate and this may explain the altered HLA-A11 serological profile exhibited by this antigen. The new allele was found in a patient with acute lymphoid leukaemia (ALL), her father and two siblings.
Alleles↗
High treatment-related mortality in cardiac amyloid patients undergoing autologous stem cell transplant.
Dose-intensive chemotherapy with PBSC support was recently reported to be feasible in cardiac amyloidosis with some patients achieving post-transplant improvement in performance status. At our center, 11 patients with symptomatic primary systemic amyloidosis and predominant cardiac involvement confirmed by biopsy or increased wall thickness on echocardiogram were evaluated for high-dose therapy. The average time from diagnosis to referral was 11 months (4-26 months). Of the 11 patients, two were not candidates for high-dose therapy, based on poor performance status. The remaining nine patients proceeded to PBSC collection. Three patients died during the mobilization period: two of rapid atrial fibrillation, and the third secondary to progressive heart failure. Six patients proceeded to transplantation. However, one died of sudden cardiac arrest the day of melphalan administration, one following hypotension related to stem cell infusion, and one of hypotensive shock the day following stem cell infusion. Three patients recovered and left the hospital, but one died of a cardiorespiratory event at home within 6 weeks of discharge. Both surviving patients demonstrate objective improvement. A decision to use high-dose therapy and stem cell support in cardiac amyloidosis must balance the substantial morbidity of the procedure with the potential benefits. Transplant regimens should avoid cardiotoxic agents such as cyclophosphamide and DMSO and patients should receive anti-arrythmic therapy.
Amyloidosis↗
Efficacy of an ondansetron orally disintegrating tablet: a novel oral formulation of this 5-HT(3) receptor antagonist in the treatment of fractionated radiotherapy-induced nausea and emesis. Emesis Study Group for the Ondansetron Orally Disintegrating Tablet in Radiotherapy Treatment.
A significant number of patients who are receiving radiotherapy experience the distressing side effects of emesis and nausea. Although prophylactic antiemetics are often given to patients who are receiving single-fraction, high-dose radiotherapy to the abdomen, a survey has revealed that antiemetic prophylaxis is not routinely offered to those receiving fractionated radiotherapy. Hence there is a need for an effective treatment of emesis for use in this group of patients. Ondansetron is an effective and well-tolerated antiemetic, which is used for the prevention of both chemotherapy and radiotherapy-induced emesis and nausea. This agent has been developed as a novel freeze-dried oral formulation. Ondansetron orally disintegrating tablets (ondODT) disperse rapidly when placed on the tongue. As the tablet does not need to be swallowed with water, it is a particularly useful formulation for patients who have difficulty with swallowing or who do not feel able to drink. This study was undertaken to investigate the efficacy of ondODT in the treatment of established emesis and nausea induced by radiotherapy. Two doses of ondODT, 8 mg and 16 mg, were compared with placebo in patients who developed emesis and/or moderate/severe nausea after receiving fractionated radiotherapy to sites located between the thorax and the pelvis. The study showed that ondODT was clinically superior to placebo in treating emesis and nausea successfully over a 12-hour period after taking the medication. There were no statistically significant differences between the two doses of ondODT. In the 2 hours after taking the study medication, patients who received ondODT (8 mg and 16 mg) had significantly fewer emetic episodes compared with those who received placebo. They also experienced significantly less nausea. In conclusion, ondODT 8 mg is effective in the treatment of radiotherapy-induced emesis and nausea and provides an effective alternative to the conventional ondansetron tablet.
Administration, Oral↗
Continuous plasmafiltration in sepsis syndrome. Plasmafiltration in Sepsis Study Group.
OBJECTIVE: To assess the effect of plasmafiltration (PF) on biochemical markers of inflammation, cytokines, organ dysfunction, and 14-day mortality in human sepsis. DESIGN: Multicenter, prospective, randomized, controlled clinical trial. SETTING: Seven university-affiliated intensive care units. PATIENTS: Thirty patients (22 adults, eight children) with new (<24 hrs) clinical evidence of infection and sepsis syndrome were enrolled. Fourteen of 30 (nine adults, five children) were randomized to PF. INTERVENTIONS: All patients received protocol-driven supportive intensive care, and those randomized to PF received continuous plasma exchange for 34 hrs using a hollow-fiber plasma filter. MEASUREMENTS AND MAIN RESULTS: Illness severity and risk of death were calculated with the Pediatric Risk of Mortality (children) and the Acute Physiology and Chronic Health Evaluation II (adults) scales. Plasma samples (0, 6, 24, and 48 hrs) were assayed for acute-phase proteins (albumin, globulin, C-reactive protein, alpha1-antitrypsin, haptoglobin), inflammatory mediators (complement fragment C3, thromboxane B2), and cytokines (interleukin-6, granulocyte colony-stimulating factor, leukemia inhibitory factor). Sieving coefficients were estimated from filtrate concentrations at 3 hrs. The two groups were matched for incidence of septic shock (13 of 14 vs. 11 of 16), refractory shock (three of 14 vs. six of 16), bacteremia (six of 14 vs. five of 16), severity of illness, and calculated risk of death (0.68 vs. 0.64). There was no difference in mortality. Eight of 14 PF patients (57%) and eight of 16 controls (50%) survived for 14 days (p = .73, Fisher's exact test). Multiple logistic regression revealed age (odds ratio, 16.4:1; 95% confidence interval, 2.12-infinity) and shock (10.6:1; 1.32-infinity) as significant predictors of death; plasmafiltration was associated with a nonsignificant reduction in the risk of death (odds ratio, 1.78:1; 95% confidence interval, 0.20-18.1). The mean (SD) number of organs failing in the first 7 days in the PF group was 2.57 (0.94) vs. 2.94 (0.85) in controls (p = .37, Mann-Whitney U test). Both groups had similarly elevated plasma concentrations of all inflammatory mediators except complement fragment C3 at study entry. Leukemia inhibitory factor was detectable in four patients only. PF did not influence mean concentrations of interleukin-6, granulocyte colony-stimulating factor, thromboxane B2, total white cell count, neutrophil count, or platelet count, but it was associated with significant reductions of alpha1-antitrypsin, haptoglobin, C-reactive protein, and complement fragment C3 in the first 6 hrs (p < .05). The sieving coefficients for all inflammatory mediators approached unity. CONCLUSIONS: PF caused a significant attenuation of the acute-phase response in sepsis. There was no significant difference in mortality, but there was a trend toward fewer organs failing in the PF group that suggests that this procedure might be beneficial.
Acute-Phase Proteins↗
Administration of low-dose aspirin to mothers with small for gestational age fetuses and abnormal umbilical Doppler studies to increase birthweight: a randomised double-blind controlled trial.
OBJECTIVE: To determine whether antenatal treatment (for > or = 14 days) with 100 mg aspirin daily, given to mothers with small for gestational age fetuses and abnormal umbilical Doppler, will increase birthweight. DESIGN: Randomised, double-blind placebo controlled trial. SETTING: A tertiary referral centre. PARTICIPANTS: Ninety-nine women, of whom 65 were treated for > or = 14 days (32 with aspirin and 33 with placebo) and comprised the study group. The entry criteria were: singleton pregnancy with ultrasound evidence of a small for gestational age fetus (abdominal circumference < 10%); previous anatomy scan < 20 weeks and no evidence of fetal abnormality; gestation between 24 and 36 weeks; umbilical artery Doppler resistance index > 95% for gestation; no previous aspirin treatment in pregnancy; and no contra-indication to aspirin treatment. RESULTS: The mean duration of treatment was 30 days for aspirin treated, and 29 for placebo. No difference was found in birthweight or other measures of fetal growth or newborn morbidity between those treated with aspirin or placebo. Compliance, assessed by thromboxane B2 analysis, showed almost complete suppression of thromboxane B2 in aspirin treated women. CONCLUSION: Low-dose aspirin did not increase birthweight in pregnancies where the fetus has abnormal umbilical Doppler and is thought to be small for gestational age.
Adult↗
Analysis of the detective quantum efficiency of a developmental detector for digital mammography.
We are developing a modular detector for applications in full field digital mammography and for diagnostic breast imaging. The detector is based on a design that has been refined over the past decade for applications in x-ray crystallography [Kalata et al., Proc. SPIE 1345, 270-279 (1990); Phillips et al. ibid. 2009, 133-138 (1993), Phillips et al., Nucl. Instrum. Methods Phys. Rev. A 334, 621-630 (1993)]. The full field mammographic detector, currently undergoing clinical evaluation, is formed from a 19 cm x 28 cm phosphor screen, read out by a 2 x 3 array of butted charge-coupled device (CCD) modules. Each 2k x 2k CCD is optically coupled to the phosphor via a fiber optic taper with dimensions of 9.4 cm x 9.4cm at the phosphor. This paper describes the imaging performance of a two-module prototype, built using a similar design. In this paper we use cascaded linear systems analysis to develop a model for calculating the spatial frequency dependent noise power spectrum (NPS) and detective quantum efficiency (DQE) of the detector using the measured modulation transfer function (MTF). We compare results of the calculation with the measured NPS and DQE of the prototype. Calculated and measured DQEs are compared over a range of clinically relevant x-ray exposures and kVps. We find that for x-ray photon energies between 10 and 28 keV, the detector gain ranges between 2.5 and 3.7 CCD electrons per incident x-ray, or approximately 5-8 electrons per absorbed x ray. Using a Mo/Mo beam and acrylic phantom, over a detector entrance exposure range of approximately 10 to 80 mR, the volume under the measured 2-d NPS of the prototype detector is proportional to the x-ray exposure, indicating quantum limited performance. Substantial agreement between the calculated and measured values was obtained for the frequency and exposure dependent NPS and DQE over a range of tube voltage from 25 to 30 kVp.
Algorithms↗
A randomised controlled trial to assess the relative benefits of large volume spacers and nebulisers to treat acute asthma in hospital.
OBJECTIVES: To compare the clinical effectiveness, acceptability, and cost benefit of administering beta2 agonists by means of a metered dose inhaler and large volume spacer with conventional nebulisers to children admitted to hospital with acute asthma. METHODS: A randomised controlled trial was conducted over five months. Sixty one children older than 3 years admitted to a large teaching hospital and a district general hospital with acute asthma completed the study. Children received either 5 mg of salbutamol up to one hourly by jet nebuliser, or up to 10 puffs of salbutamol 100 microg by means of a metered dose inhaler and spacer up to one hourly. RESULTS: Median hospital stay was 40 hours in the nebuliser group and 36.5 hours in the spacer group. Asthma disability scores at two weeks after discharge were significantly improved in the spacer group. Drug costs were pound 14.62 less for each patient in the spacer group. CONCLUSIONS: Large volume spacers are an acceptable, cost effective alternative to nebulisers in treating children admitted with acute asthma, provided that the children can use the mouthpiece, and symptoms are not severe. Their use facilitates effective home treatment by parents, with subsequent reduction in morbidity and re-admission rates.
Acute Disease↗