Acute medicine teaching in an undergraduate medical curriculum: a blended learning approach.

BACKGROUND: Acute medical management is an important component of the Modernising Medical Careers (MMC) project which has recently been implemented in the UK. A web-based interactive course in acute medicine has been developed which complements the clinical teaching provided to senior medical students at the University of Glasgow. A study was undertaken to evaluate the teaching and assess the knowledge of acute medicine among final year medical students using an online questionnaire. METHODS: The undergraduate medical school Virtual Learning Environment (VLE) was constructed using the Moodle learning management system. The online questionnaire was constructed as part of the interactive acute medicine course hosted on the VLE. Final year students using this course were asked to complete the questionnaire anonymously. A 5-point Likert scale was used to assess different aspects of acute medical management and evaluate the teaching. RESULTS: From 210 students using the website, 99 (47.1%) completed the online questionnaire. Nephrology and neurology were identified as the most challenging specialties in acute medicine. The areas of acute management in which students felt they lacked most knowledge were drug overdose and acute renal failure. Drug prescribing was also identified as an area of the curriculum requiring further development. CONCLUSIONS: This approach to blended learning is popular with our medical students. Online evaluation has helped with curriculum development and, by identifying important areas of acute medicine teaching that can be improved, is feeding into our curriculum revision.

FasL gene therapy: a new therapeutic modality for head and neck cancer.

In this study, we investigated the in vitro and in vivo efficacy of Fas ligand (FasL) gene therapy for the treatment of head and neck cancer. Three head and neck squamous cell carcinoma (HNSCC) cell lines (SCC-1, SCC-12, and SCC-14a) were treated with the Fas agonist CH-11, a monoclonal antibody to the Fas receptor, or with a replication-incompetent adenovirus (AdGFPFasL) expressing a modified murine Fas ligand gene fused to green fluorescent protein (GFP). A replication-incompetent adenovirus containing the GFP gene alone was used as a control for viral transduction toxicity (AdGFP). Cell death was quantified using a tetrazolium-based (MTS) assay. Cells were analyzed by flow cytometry to determine the expression of adenoviral and Fas receptors on the surface of the cells. Our results showed that the head and neck cancer cell lines are resistant to cell death induction when treated with the anti-Fas monoclonal antibody CH-11. This resistance can be overcome with AdGFPFasL, which was able to induce cell death in all three cell lines. Apoptosis induction was demonstrated using Western blotting by evaluating poly(ADP-ribose) polymerase, and caspase 9 cleavages. In addition, intratumoral injections of AdGFPFasL into SCC-14a xenografts induced significant growth suppression of tumors, indicating that FasL gene therapy may provide a new efficient therapeutic modality for HNSCC that is worthy of a clinical trial.

Combined therapeutic use of AdGFPFasL and small molecule inhibitors of ceramide metabolism in prostate and head and neck cancers: a status report.

As of January 2005, there were 1020 gene therapy clinical trials ongoing worldwide with 675 or 66.2% devoted to cancer gene therapy. The majority are occurring in the US and Europe (http://www.wiley.co.uk/genetherapy/clinical/). At the present time, to our knowledge there are no trials that employ gene delivery of Fas Ligand (FasL). As an important note, and in contrast to somatic cell therapy trials, there are no reported deaths due to therapeutic vector administration in any cancer gene therapy trial. That said, from our studies and from the published literature, the issue of gene delivery remains the major obstacle to successfully employing gene therapy for cancer treatment. Numerous laboratories are studying this with many different approaches. My co-workers and I have focused on the delivery issue by using various approaches that address tumor targeting and transgene expression. In addition, we are focusing on enhancing tumor cell killing via the bystander effect and through use of small molecules to enhance bystander activity.

Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study.

BACKGROUND: We examined the development of new diabetes mellitus in men aged 45 to 64 years during the West of Scotland Coronary Prevention Study. METHODS AND RESULTS: Our definition of diabetes mellitus was based on the American Diabetic Association threshold of a blood glucose level of >/=7.0 mmol/L. Subjects who self-reported diabetes at baseline or had a baseline glucose level of >/=7.0 mmol/L were excluded from the analyses. A total of 5974 of the 6595 randomized subjects were included in the analysis, and 139 subjects became diabetic during the study. The baseline predictors of the transition from normal glucose control to diabetes were studied. In the univariate model, body mass index, log triglyceride, log white blood cell count, systolic blood pressure, total and HDL cholesterol, glucose, and randomized treatment assignment to pravastatin were significant predictors. In a multivariate model, body mass index, log triglyceride, glucose, and pravastatin therapy were retained as predictors of diabetes in this cohort. CONCLUSIONS: We concluded that the assignment to pravastatin therapy resulted in a 30% reduction (P:=0.042) in the hazard of becoming diabetic. By lowering plasma triglyceride levels, pravastatin therapy may favorably influence the development of diabetes, but other explanations, such as the anti-inflammatory properties of this drug in combination with its endothelial effects, cannot be excluded with these analyses.

Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial.

PURPOSE: To evaluate the effectiveness and safety of samarium-153 (153Sm) lexidronam (EDTMP) in a double-blind, placebo-controlled study. PATIENTS AND METHODS: Patients with painful bone metastases secondary to a variety of primary malignancies were randomized to receive 153Sm-EDTMP 0.5 or 1.0 mCi/kg, or placebo. Treatment was unblinded for patients who did not respond by week 4, with those who had received placebo eligible to receive 1.0 mCi/kg of active drug in an open-label manner. Patient and physician evaluations were used to assess pain relief, as was concurrent change in opioid analgesia. RESULTS: One hundred eighteen patients were enrolled onto the study. Patients who received 1.0 mCi/kg of active drug had significant reductions in pain during each of the first 4 weeks in both patient-rated and physician-rated evaluations. Pain relief was observed in 62% to 72% of those who received the 1.O-mCi/kg dose during the first 4 weeks, with marked or complete relief noted in 31% by week 4. Persistence of pain relief was seen through week 16 in 43% of patients who received 1.0 mCi/kg, of active drug. A significant correlation (P = .01) was observed between reductions in opioid analgesic use and pain scores only for those patients who received 1.0 mCi/kg 153Sm-EDTMP. Bone marrow suppression was mild, reversible, and not associated with grade 4 toxicity. CONCLUSION: A single dose of 1.0 mCi/kg of 153Sm-EDTMP provided relief from pain associated with bone metastases. Pain relief was observed within 1 week of administration and persisted until at least week 16 in the majority of patients who responded.

Pathophysiologic assessment of left ventricular hypertrophy and strain in asymptomatic patients with essential hypertension.

To investigate the significance of the electrocardiographic (ECG) pattern of left ventricular hypertrophy and strain, two groups of asymptomatic patients with essential hypertension were compared. The patients were similar in terms of age, smoking habit, serum cholesterol and blood pressure levels, but differed in the presence (Group I, n = 23) or absence (Group II, n = 23) of the ECG pattern of left ventricular hypertrophy and strain. Group I patients had significantly more episodes of exercise-induced ST segment depression (14 versus 4, p less than 0.05) and reversible thallium perfusion abnormalities (11 of 23 versus 3 of 23, p less than 0.05) despite similar exercise capacity and absence of chest pain. Nonsustained ventricular tachycardia was detected on 24 h ambulatory ECG monitoring in two patients in Group I, but no patient in Group II. Coronary arteriography performed in 20 Group I patients demonstrated significant coronary artery disease in 8 patients. This study has shown that there is a subgroup of hypertensive patients with ECG left ventricular hypertrophy and strain who have covert coronary artery disease. This can be detected by thallium perfusion scintigraphy, and may contribute to the increased risk known to be associated with this ECG abnormality.

Successful management of Graves' disease in a patient undergoing regular dialysis therapy.

Classic Graves' disease associated with thyroid-stimulating hormone receptor antibodies developed in a woman undergoing regular hemodialysis for uremia from chronic pyelonephritis. Her condition responded well to treatment initially with carbimazole and then an ablative dose of sodium iodide I 131 therapy. To our knowledge this is only the second documented case of hyperthyroidism in a patient with chronic renal failure, and it demonstrates that conventional forms of therapy are efficacious and safe.

Erythrocyte glutathione balance and membrane stability during preeclampsia.

This study aimed to determine whether oxidative damage to the erythrocyte occurs in preeclampsia, and relates to disease severity. The oxidative status of intact erythrocytes from preeclamptic patients and normal pregnant women was determined using spin echo 1H-NMR, which measures both the concentration and redox state of intracellular glutathione. Previous studies of preeclampsia have only measured total glutathione levels. Membrane fragility was determined from the degree of lysis caused by incubation in hypotonic saline. Erythrocytes from moderate-severe preeclamptic patients underwent more lysis than erythrocytes from control pregnant women (p < .05) or mild preeclamptic patients. It is suggested that increased lysis results from oxidative damage to the erythrocyte membrane, causing a decrease in membrane fluidity and reducing its ability to withstand osmotic changes. Intracellular glutathione was more oxidized in erythrocytes from pregnant women compared to nonpregnant controls (p < .05), and there was a less significant trend toward more oxidized glutathione with increasing severity of preeclampsia. The moderate-severe group showed a clear division in glutathione redox status: some patients had very oxidized glutathione while others had a normal redox balance. This novel finding suggests that some patients may be unusually susceptible to erythrocyte glutathione oxidation, possibly leading to general cellular damage, in particular HELLP Syndrome.

Antioxidants: their role in pregnancy and miscarriage.

The aim of this study was to examine the role of antioxidants within the normal menstrual cycle, in healthy pregnancy, and in women suffering first-trimester miscarriage. The antioxidants chosen comprised of two from peripheral blood-plasma thiol and ceruloplasmin-and two extracellular parameters-superoxide dismustase (SOD) and red cell lysate thiol. We found that antioxidant levels varied little throughout the menstrual cycle. Pregnancies that went successfully to term were associated with increased levels of ceruloplasmin and SOD early in the first trimester. These changes were thought to offer the cell protection from the damage caused by the increased oxidative stress associated with pregnancy. First-trimester miscarriage was associated with significantly reduced levels of SOD. A subgroup of patients who miscarried in their first pregnancy, but whose second pregnancies were successful, had higher levels of plasma thiol and significantly reduced levels of red cell lysate thiol in the on-going pregnancy compared to levels at the time of miscarriage. Miscarriage and pregnancy appear to be associated with increased oxidative stress. In a successful pregnancy, however, changes occurred within the peripheral blood that offered protection from oxidant attack.

Lumbar transplant of neurons genetically modified to secrete brain-derived neurotrophic factor attenuates allodynia and hyperalgesia after sciatic nerve constriction.

Chronic delivery of anti-nociceptive molecules by means of cell grafts near the pain processing centers of the spinal cord is a newly developing technique for the treatment of neuropathic pain. The rat neuronal cell line, RN33B, derived from E13 rat brainstem raphe and immortalized with the SV40 temperature-sensitive allele of large T antigen (tsTag), was transfected with rat brain-derived neurotrophic factor cDNA (BDNF), and the BDNF-synthesizing cell line, 33BDNF.4, was isolated. The 33BDNF.4 cells synthesized mature BDNF protein at permissive temperature (33 degrees C), when the cells were proliferating, and during differentiation at non-permissive temperature (39 degrees C) in vitro. The bio-active BDNF protein was also secreted by the cells during both growth conditions, as measured by ELISA analysis of BDNF content and secretion. The bio-activity of the BDNF in 33BDNF.4 cell conditioned media was assessed by neurite outgrowth from E15 dorsal root ganglion (DRG) cultures. A control cell line, 33V1, transfected with the vector alone, did not synthesize or secrete any significant BDNF at either growth condition. Both cell lines were used as grafts in a model of chronic neuropathic pain induced by unilateral chronic constriction injury (CCI) of the sciatic nerve. Pain-related behaviors, including cold and tactile allodynia and thermal and tactile hyperalgesia, were evaluated after CCI in the affected hindpaw. When 33BDNF.4 and 33V1 cells were transplanted in the lumbar subarachnoid space of the spinal cord 1 week after CCI, they survived greater than 7 weeks on the pia mater around the spinal cord and the 33BDNF.4 cells continued to synthesize BDNF in vivo. Furthermore, the tactile and cold allodynia and tactile and thermal hyperalgesia induced by CCI was significantly reduced during the 2-7 week period after grafts of 33BDNF.4 cells. The maximal effect on chronic pain behaviors with the BDNF grafts occurred 2-3 weeks after transplant and the anti-nociceptive effects of the BDNF cell grafts was permanent. Transplants of the control 33V1 cells had no effect on the allodynia and hyperalgesia induced by CCI and these cells did not synthesize BDNF in vivo. These data suggest that a chronically applied, low local dose of BDNF supplied by transplanted cells near the spinal dorsal horn was able to reverse the development of chronic neuropathic pain following CCI. The use of neural cell lines that are able to deliver anti-nociceptive molecules, such as BDNF, in a model of chronic pain offers a novel approach to pain management and such 'biologic minipumps' can be developed for safe use in humans.

The "hot patella" sign: is it of any clinical significance? Concise communication.

The presence of the "hot patella" sign was evaluated in a prospective study of 200 consecutive bone scans, and in a review of scans from 148 patients with various metabolic bone disorders and 61 patients with lung carcinoma. The incidence was found to be 31%, 26% and 31% respectively. This sign is an extremely common scan finding and may be seen in association with a wide variety of disorders. It is concluded that this sign cannot be considered to be of diagnostic value.

Digital filtering of the bladder in SPECT bone studies of the pelvis.

A data processing technique for the removal of bladder activity from single photon emission computed tomographic bone studies of the pelvis has been developed. The method involves the replacement of count values in the bladder on all projection views by data which are representative of the activity in surrounding structures. Reconstruction is then performed using the amended set of projection views. The method was tested by examining a group of 13 patients referred for investigation of avascular necrosis of the femoral head. Significant improvements in image quality were observed, particularly with respect to the level of artifact production, which increased the number of cases in which a confident and correct diagnosis was made.

Relapse of Graves' disease after medical therapy: predictive value of thyroidal technetium-99m uptake and serum thyroid stimulating hormone receptor antibody levels.

In 49 patients with Graves' disease, the 20-min thyroidal uptake of 99mTc and serum levels of thyroid stimulating hormone (TSH) receptor antibody were estimated at presentation and at intervals during a 1-yr course of carbimazole and triiodothyronine. In the 12 mo after cessation of therapy, 29 patients developed recurrent thyrotoxicosis. Thyroidal 99mTc uptake had a poor predictive value for recurrence of thyrotoxicosis, both at presentation and during therapy. A very high level of TSH receptor antibody was present in seven patients at presentation, all of whom relapsed on withdrawing therapy. An abnormal value of TSH receptor antibody at the end of the course of medical therapy was present in 24/29 (83%) patients who relapsed and in 1/20 (5%) patients who remained euthyroid 1 yr after stopping antithyroid drugs.

Can the extent of coronary artery disease be predicted from thallium-201 myocardial images?

The accuracy with which the extent of coronary artery disease can be predicted from stress thallium-201 myocardial images has been assessed in 81 patients with chest pain. Whereas the appearance of the myocardial images was both a sensitive means of detecting coronary artery disease (images abnormal in 43 of 47 patients with abnormal coronary arteriograms) and specific in excluding it (images normal in 31 of 34 patients with normal arteriograms), there was poor correlation between the extent of disease predicted from the Tl-201 images and the findings at arteriography. It is concluded that although stress Tl-201 myocardial imaging is a useful method for the noninvasive diagnosis of coronary artery disease, it cannot be relied upon to predict the number of abnormal vessels.

Bone scan findings in hypervitaminosis D: case report.

Bone scans in three patients showed generalized symmetrical increased uptake of radiopharmaceutical by the skeleton and absent or faint kidney images. It is thought that these appearances may be attributable to excess vitamin D, but other possible contributing factors, including the presence of renal osteodystrophy, are discussed.

The role of bone scanning in osteomalacia.

The presence of eight "metabolic features" was assessed on the bone scintigrams of ten patients with osteomalacia. In all of these bone images, sufficient features were present to strongly suggest a metabolic disorder. There scintiphotos were included in a controlled blind study using 30 normal bone scans and 20 scans of metastatic disease. Nine of the ten metabolic bone images were correctly identified by two independent observers. Skeletal uptake of radiotracer, expressed as bone-to-soft tissue ratio, was significantly higher in the osteomalacic patients than in a group of 80 controls.

ECG gating of thallium-201 myocardial images: effect on detection of ischemic heart disease.

Using the angiographic findings as the standard, we have examined the sensitivity and specificity of ECG-gated static thallium-201 myocardial images in 54 patients undergoing selective coronary arteriography. Gated and nongated images, each in anterior, 45 degrees LAO, and 65 degrees LAO projections, were processed by interpolative background subtraction. They were then analyzed separately by four independent observers who were unaware of patient identity, the results of coronary arteriography, and which studies were gated or nongated. No significant differences were observed between the gated and nongated images regarding sensitivity or specificity, the detection rate for reversible myocardial ischemia, the accuracy of prediction of arteriographic extent of disease, or the degree of inter- or intraobserver variability. We conclude that ECG-gated acquisition of T1-201 images does not produce any significant advantages, at least when interpolative background subtraction is used.

A clinical comparison of Tc-99m HEDP and Tc-99m MDP in the detection of bone metastases: concise communication.

We have compared bone scintigrams made with Tc-99m-tagged HEDP (1-hydroxyethylidene diphosphonate)and MDP (methylene diphosphonate), the former at 4 hr after injection, the latter at both 2 and 4 hr. In 17 patients with skeletal metastases, there was no significant difference in lesion count or scan quality between the 4-hr images. The tumor-to-bone ratio (T/B) was significantly higher with Tc-HEDP (p less than 0.02). Lesion detection rate and T/B ratios were both lower with Tc-MDP at 2 hr when compared with the 4-hr values for both Tc-HEDP (p less than 0.02, p less than 0.005) and Tc-MDP (p less than 0.02, p less than 0.01). The 4-hr Tc-MDP scan was of significantly higher quality than the 2 hr Tc-MDP scan (p less than 0.01). Although Tc-HEDP produces a higher T/B ratio at 4 hr, the present study does not suggest that either agent is superior in clinical practice.