Assessment of factual recall and higher-order cognitive domains in an open-book medical school examination.

Open-book examinations (OBEs) will likely become increasingly important assessment tools. We investigated how access to open-book resources affected questions testing factual recall, which might be easy to look-up, versus questions testing higher-order cognitive domains. Few studies have investigated OBEs using modern Internet resources or as summative assessments. We compared performance on an examination conducted as a traditional closed-book exam (CBE) in 2019 (N = 320) and a remote OBE with free access to Internet resources in 2020 (N = 337) due to COVID-19. This summative, end-of-year assessment focused on basic science for second-year medical students. We categorized questions by Bloom's taxonomy ('Remember', versus 'Understand/Apply'). We predicted higher performance on the OBE, driven by higher performance on 'Remember' questions. We used an item-centric analysis by using performance per item over all examinees as the outcome variable in logistic regression, with terms 'Open-Book, 'Bloom Category' and their interaction. Performance was higher on OBE questions than CBE questions (OR 2.2, 95% CI: 2.14-2.39), and higher on 'Remember' than 'Understand/Apply' questions (OR 1.13, 95% CI: 1.09-1.19). The difference in performance between 'Remember' and 'Understand/Apply' questions was greater in the OBE than the CBE ('Open-Book' * 'Bloom Category' interaction: OR 1.2, 95% CI: 1.19-1.37). Access to open-book resources had a greater effect on performance on factual recall questions than higher-order questions, though performance was higher in the OBE overall. OBE design must consider how searching for information affects performance, particularly on questions measuring different domains of knowledge.

Aneuploidy involving chromosome 1 may be an early predictive marker of intestinal type gastric cancer.

Intestinal type gastric cancer is a significant cause of mortality, therefore a better understanding of its molecular basis is required. We assessed if either aneuploidy or activity of the oncogenic transcription factor nuclear factor kappa B (NF-kappaB), increased incrementally during pre-malignant gastric histological progression and also if they correlated with each other in patient samples, as they are both induced by oxygen free radicals. In a prospective study of 54 (aneuploidy) and 59 (NF-kappaB) consecutive patients, aneuploidy was assessed by interphase fluorescent in situ hybridisation (FISH) for chromosome 1. NF-kappaB was assessed by expression of interleukin-8 (IL-8), and in a subset, by immunohistochemistry (IHC) for active p65. Aneuploidy levels increased incrementally across the histological series. 2.76% of cells with normal histology (95% CI, 2.14-3.38%) showed background levels of aneuploidy, this increased to averages of 3.78% (95% CI, 3.21-4.35%), 5.89% (95% CI, 3.72-8.06%) and 7.29% (95% CI, 4.73-9.85%) of cells from patients with gastritis, Helicobacter pylori positive gastritis and atrophy/intestinal metaplasia (IM) respectively. IL-8 expression was only increased in patients with current H. pylori infection. NF-kappaB analysis showed some increased p65 activity in inflamed tissues. IL-8 expression and aneuploidy level were not linked in individual patients. Aneuploidy levels increased incrementally during histological progression; were significantly elevated at very early stages of neoplastic progression and could well be linked to cancer development and used to assess cancer risk. Reactive oxygen species (ROS) induced in early gastric cancer are presumably responsible for the stepwise accumulation of this particular mutation, i.e. aneuploidy. Hence, aneuploidy measured by fluorescent in situ hybridisation (FISH) coupled to brush cytology, would be worthy of consideration as a predictive marker in gastric cancer and could be clinically useful in pre-malignant disease to stratify patients by their cancer risk.

Heterotopic salivary gland presenting as a supra-clavicular swelling.

A 5-month-old female was referred to the paediatric surgery clinic with a neck swelling in the right supra-clavicular region. This was thought clinically to be cystic hygroma. Pathology showed an ectopic salivary gland. This should be added to the list of differential diagnoses of neck swelling in childhood.

Nutritional deficiencies after bariatric surgery.

A current review of nutritional complications following bariatric procedures is presented, focusing on the most common and clinically important deficiencies. A brief outline of nutritional supplementation protocol is presented, highlighting the need for a standardized, national or international set of guidelines for pre- and postoperative nutritional screening and appropriate supplementation.

Effects of graft-versus-host reaction on inhibition of tumor growth in vivo and on tumor cytotoxicity in vitro.

In DA X Wistar F1 rats, growth of 10(4) Wistar-specific Sp 1 carcinoma cells s.c. was commonly prevented by a mild subclinical graft=versus-host reaction produced by injecting 50 X 10(6) Wistar spleen cells i.p. either concurrently with the tumor or 7 to 14 days previously, Spleen cells alone had no effect on established tumor, but their injection on Day 14 significantly reduced the recurrence rate after excision of tumor on Day 21. In vitro tests in tumor-bearing rats with graft-versus-host reactions showed increased spleen lymphocyte and serum cytotoxicity; these mechanisms may inhibit tumor growth in vivo. Because Wistar lymphocytes and Sp 1 cells are syngeneic, inhibition of tumor cannot be due to allograft rejection but is probably an effect of increased host immunoreactivity during the graft-versus-host reaction.

The sensitization of near-ultraviolet radiation killing of mammalian cells by the sunscreen agent para-aminobenzoic acid.

The wavelengths of sunlight considered to be responsible for erythema and skin cancer formation are in the range 290-340 nm. Formulated sunscreens usually contain an agent that absorbs in this wavelength region, and one of the most widely used is para-aminobenzoic acid (PABA). Previous work has demonstrated the sensitization by PABA of the lethal and mutagenic effects of near-ultraviolet (UV) radiation in a model bacterial system. Experiments with the mouse lymphoma L5178Y cell line have now demonstrated sensitization by PABA of the lethal effect of near-UV radiation, the extent of which, after correction for absorption of UV radiation by PABA, bears a direct relationship to PABA concentration. The limitations of these results in predicting the response of human skin to the presence of PABA during exposure to UV radiation is emphasized.

Mapping the melatonin receptor. 5. Melatonin agonists and antagonists derived from tetrahydrocyclopent[b]indoles, tetrahydrocarbazoles and hexahydrocyclohept[b]indoles.

Tetrahydrocyclopent[b]indoles, tetrahydrocarbazoles, and hexahydrocyclohept[b]indoles have been prepared as melatonin analogues to investigate the nature of the binding site of the melatonin receptor. The affinity of analogues was compared in a radioligand binding assay using chicken brain membranes and agonist and antagonist potency measured in clonal Xenopus laevis melanophore cells. Comparison of the N-acyl-3-amino-6-methoxytetrahydrocarbazoles (2) with N-acyl-4-(aminomethyl)-6-methoxy-9-methyltetrahydrocarbazoles (9) showed that the latter have much higher binding affinities for the chicken brain receptor. Comparison of N-acyl-1-(aminomethyl)-7-methoxy-4-methyltetrahydrocyclopent[b]ind oles (10), 6-methoxytetrahydrocarbazoles (9), and N-acyl-10-(aminomethyl)-2-methoxy-5-methylhexahydrocyclohept[b]ind oles (11) showed that the tetrahydrocarbazoles had the highest binding affinity with the cyclohept[b]indoles and the cyclopent[b]indoles having rather lower affinities. All of these observations are in agreement with our postulated model of melatonin orientation at the binding pocket in which the 3-amidoethane side chain is in a conformation close to the 5-methoxyl group, as is shown in the X-ray crystallographic structure of 9m and in the energy-minimized computed structures. Separation of the enantiomers of members from each of these three systems was accomplished by chiral HPLC. It was found that in all cases the (-)-enantiomer had a higher binding affinity than the (+)-enantiomer. An X-ray crystallographic analysis of the two enantiomers of 9a showed that the (+)-enantiomer had the (R) absolute stereochemistry. Since the sign of the Cotton curves, determined from circular dichroism studies, was the same for all (+)-enantiomers, it is assumed that the absolute stereochemistry at these centers is identical. In the Xenopus melanophore assay, the tetrahydrocarbazoles 2 (R = H) were mainly weak antagonists, while those with R = OMe were agonists. The biological behavior of the tetrahydrocarbazoles 9 (R = H) depended on R1, some being agonists and some antagonists, whereas those with R = OMe were generally agonists. Variation of the R and R1 groups in compounds of type 9 produced both agonists and antagonists. The tetrahydrocylopentaindoles 10 had similar biological properties to the corresponding analogues of 9, but the hexahydrocycloheptaindoles 11 showed a much greater propensity to be antagonists. In all cases the (S)-enantiomers were found to be more potent agonists than the (R)-enantiomers.

Studies on the vasoconstrictor action of melatonin and putative melatonin receptor ligands in the tail artery of juvenile Wistar rats.

1. In this study we compared the vasoconstrictor activity of melatonin in rat isolated tail artery using two different recording systems, the Halpern pressure myograph and the Halpern-Mulvany wire myograph, with the view to determining a reliable method for obtaining pharmacological data on vascular melatonin receptors. In addition, we characterized the melatonin receptor in this preparation, using analogues of melatonin, and examined the activity of various naphthalenic derivatives with biological activity in non-vascular models of melatonin receptors. 2. Using the Halpern pressure myograph, cumulative addition of melatonin (0.1 nM to 1 microM) produced direct vasoconstriction (19.3+/-6.4% reduction in lumen diameter, n=5) in five of 11 pressurized segments, with pEC50 of 9.14+/-0.17. Similarly, non-cumulative application of melatonin caused vasoconstriction (19.7+/-4.6% reduction in lumen diameter, n=7) in seven of 20 preparations examined with pEC50 of 8.74+/-0.26. The selective alpha2-adrenoceptor agonist, UK-14304 (5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline bitartrate), produced vasoconstriction in all 'melatonin-insensitive' preparations. 3. Melatonin (0.1 nM to 1 microM) failed to elicit isometric contractions of tail artery segments in the Halpern wire myograph, but produced concentration-dependent potentiation of electrically-evoked, isometric contractions (maximum effect of 150-200% enhancement) when applied either noncumulatively (seven of seven preparations) or cumulatively (four of seven preparations). The pEC50 value of melatonin (non-cumulative) was 8.50+/-0.10 (n=7) which was not different from that obtained in the pressure myograph. All further experiments were conducted using a non-cumulative protocol against electrically-evoked, isometric contractions. 4. Based on the pEC50 values for the melatonin analogues examined, the pharmacological profile for the enhancement of electrically-evoked contractions was 2-iodomelatonin > 6-chloromelatonin > or = (-)-AMMTC > or = S21634 > or = melatonin > or = S20098 > S20242 > or = S20304 > 6-hydroxymelatonin > S20932 > (+)-AMMTC > N-acetyl-5-HT. Our data suggests the vascular receptor belongs to the MEL1-like subtype. All the indole-based analogues of melatonin, 2-iodomelatonin, (-)-AMMTC, (+)-AMMTC, S20932, 6-chloromelatonin, 6-hydroxymelatonin and N-acetyl-5-HT, behaved as full agonists. All the naphthalenic derivatives examined, S21634, S20098, S20242 and S20304 behaved as partial agonists relative to melatonin. 5. The naphthalenic-based antagonists, S20928 and S20929, did not modify electrically-evoked, isometric contractions of the tail artery, but produced a parallel, rightward displacement of the melatonin concentration-response curve. Based upon the effect of 1 microM S20928 and S20929, the estimated pK(B) values for these antagonists were 7.18+/-0.25 (n=4) and 7.17+/-0.25 (n=5), respectively. 6. We demonstrated that enhancement of electrically-evoked, isometric contractions of the rat isolated tail artery (using the Halpern-Mulvany wire myograph) is a simple and reproducible model for assessing the activity of putative agonists, partial agonists and antagonists at vascular melatonin receptors. Pharmacological characterization of the receptor suggests the presence of a MEL1-like subtype.

Lead exposure in young children from dust and soil in the United Kingdom.

A survey of metals in United Kingdom dusts and soils has confirmed widespread lead contamination with a geometric mean value for lead in surface (0-5 cm) garden soils of 266 micrograms/g and in housedusts of 561 micrograms/g (excluding old mining areas). A subsequent detailed survey of 97 householders in Birmingham with 2-year-old children showed dust lead loading in the home environment to be an important predictor of blood lead concentrations in young children, when both variables fell within the normal range for the U.K. The total estimated lead uptake by the young child was 36 micrograms/day of which 1 microgram was by inhalation and 35 micrograms by ingestion.

Thin basement membranes in minimally abnormal glomeruli.

The light microscopic, immunofluorescence, and electron microscopic appearances of renal biopsy specimens were reviewed and correlated with the clinical and laboratory findings in 61 patients in whom the findings were initially considered to be either normal or to show only minor non-specific abnormalities. In all cases this reassessment included quantitative measurement of glomerular basement membrane thickness by an orthogonal intercept technique. On the basis of the indication for biopsy, patients were classified into three groups: those with haematuria (group I, n = 41); those with a minor degree of proteinuria (group II, n = 16); and those without any urinary abnormality but in whom possible renal disease as a result of systemic disease was suspected (group III, n = 6). About half of the patients with haematuria had significantly thinner glomerular basement membranes than those in the other two groups, irrespective of the variable selected for assessment, and in three this was confirmed in follow up biopsy specimens. Follow up for up to eight years showed that in patients either with or without thin basement membranes haematuria commonly persisted, but the long term outlook in all three groups was otherwise good and no patient developed impaired renal function.

Radioligand binding affinity and biological activity of the enantiomers of a chiral melatonin analogue.

Melatonin, a hormone secreted by the pineal gland, can act on the central circadian oscillator in the suprachiasmatic nucleus of the hypothalamus. It has been proposed that melatonin or its analogues may be useful in restoring disturbed circadian rhythms in jet-lag, shift-work and some blind subjects, and as sleep-promoting agents. In the present study, the (-)- and (+)-enantiomers of N-acetyl-4-aminomethyl-6-methoxy-9-methyl-1,2,3,4-tetrahydrocarbazole (AMMTC) were separated and tested. The affinity of the enantiomers at the specific 2-[125I]iodomelatonin binding site in chick brain membranes was compared in competition assays, and their biological activity in a specific melatonin receptor bioassay, aggregation of pigment granules in Xenopus laevis melanophores. The (-)-enantiomer of AMMTC was 130-fold and 230-fold more potent than the (+)-enantiomer in competition radioligand binding assays and melanophores, respectively. Both enantiomers are melatonin receptor agonists; (-)-AMMTC is slightly more potent than melatonin itself. As the tetrahydrocarbazole nucleus holds the C-3 amido side-chain of AMMTC in a restricted conformation, the analogues will be useful in modelling the melatonin receptor binding site.

Primary retinopathy in scrapie in mice deprived of light.

Rodents infected with some strains of scrapie develop a severe retinopathy in which the photoreceptor cells are destroyed. The possibility that this results from light-induced damage as a secondary consequence of the disease was tested by maintaining scrapie-infected albino mice in total darkness. Photoreceptor loss occurred in terminal scrapie-infected mice maintained in both total darkness and in normal lighting conditions establishing that the retinopathy is a primary lesion with this strain of scrapie agent.

Control of glaucoma by reduced dosage guanethidine-adrenaline formulation.

The effect of formulations of guanethidine and adrenaline of different composition has been tested in rabbits and in patients with glaucoma. The concentrations of guanethidine and adrenaline used for the rabbits were 5.0% and 1.0%; 2.5% and 0.5%; 1.0% and 0.2%; 0.5% and 0.1%. All except the lowest combination were equally effective in the magnitude of the decrease in intraocular pressure brought about and in their duration of activity. Two formulations containing guanethidine and adrenaline at concentrations of 3.0% and 0.5% and 1.0% and 0.2% respectively (formulated as Ganda drops by Smith and Nephew Pharmaceuticals Ltd) were tested in a blind, cross-over, short-term clinical trial on 20 patients. The drops containing the lower concentration of drugs were as effective as those of higher concentration. These results lead us to believe that most patients who respond to this treatment could be put on a reduced dosage regimen, which should result in a decreased incidence and severity of side effects.

Effect of adrenaline and guanethidine in reducing intraocular pressure in rabbits' eyes.

The effect of Adrenaline 0.5 per cent and Guanethidine 2.5 per cent alone and in combination in reducing intraocular pressure in rabbits has been studied. Six rabbits were used and the efficiencies of 5 different dosage protocols was estimated both as intensity and duration of activity. The 5 dosage protocols were Adrenaline alone; Guanethidine alone; Adrenaline and Guanethidine together; Adrenaline followed in 30 min by ?Guanethidine; and Guanethidine followed in 30 min by Adrenaline. The single formulation containing both drugs appeared to be at least as efficient as the others. Eye drops containing 1 per cent Adrenaline and 5 per cent Guanethidine having sufficient stability for normal use have therefore been formulated.

Local renal graft-versus-host reaction: sequential ultrastructural study.

A sequential study has been made of the ultrastructure of local renal graft-versus-host reactions produced in cyclophosphamide-pretreated rats by injection of either allogeneic or xenogeneic (mouse) spleen cells beneath the renal capsule. Early in the reaction, immunoblasts were seen between the outer cortical tubules, and there was associated interstitial oedema and tubular degeneration. In places, several small lymphocytes were observed clustered around and in close cytoplasmic contact with individual immunoblasts, perhaps representing interaction between donor and host cells. As the reaction proceeded, the number of lymphoid cells increased by immigration from peritubular vessels. Some tubules were invaded by lymphocytes but this was not closely related to the development of tubular injury. The reaction was maximum at one week and then decreased. Now, there was greater diversity of cells including macrophages, plasma cells and eosinophils, while many lymphoid cells became necrotic. It is concluded that most of the renal parenchymal injury is due to chemical mediators liberated from the infiltrating cells rather than to ischaemia or direct cytoplasmic interaction between leucocytes and tubular epithelium.

Gold nephropathy.

Nephropathy with proteinuria is an occasional complication of gold therapy for rheumatoid arthritis and is considered to be due to an immune hypersensitivity reaction. Three patients are described in whom the structural changes typical of gold nephropathy were demonstrated by electron microscopy of renal biopsies. There was early membranous glomerular nephropathy with multiple sub-epithelial deposits of immune complexes. In one case these were shown by immunofluorescence to contain IgG and complement. Proximal tubules contained characteristic dense granular intracytoplasmic gold inclusions, best demonstrated by electron microscopy of unstained sections.

Two ELISAs to detect anti-neutrophil cytoplasm antibodies (ANCA) in various vasculitides.

Anti-neutrophil cytoplasm antibodies (ANCA) are present in the serum of patients with Wegener's granulomatosis, microscopic polyarteritis, and some other small vessel vasculitides. There are at least 2 different anti-neutrophil cytoplasm antibodies identified by their distinctive cytoplasmic staining patterns on indirect immunofluorescence examination. The only antigen identified to date is myeloperoxidase which has a perinuclear distribution on alcohol-fixed neutrophils and monocytes. We have established an ELISA that detects all anti-neutrophil cytoplasm antibodies and one specific for anti-myeloperoxidase antibodies. In the ELISA for anti-neutrophil cytoplasm antibodies, all sera with diffuse cytoplasmic or perinuclear neutrophil staining on indirect immunofluorescence examination bound at levels greater than the normal range (34%, m + 4SD). Three convalescent sera that were negative by indirect immunofluorescence examination were also negative in the assay. Positive sera could be detected at a dilution of 2 and inhibition studies showed that the binding was specific for the neutrophil extract. However, the presence of anti-neutrophil antibodies (ANA), anti-mitochondrial antibodies or immune complexes resulted occasionally in binding in the positive range. Where positive binding was noted in non-vasculitic segmental necrotizing glomerulonephritis, the binding could not be inhibited by pre-incubation with the neutrophil extract. The ELISA for ANCA is a sensitive, objective screening technique that can be performed in parallel with the assay for anti-glomerular basement antibodies to exclude the presence of anti-neutrophil cytoplasm antibodies in patients presenting with rapidly progressive glomerulonephritis. The ELISA for anti-myeloperoxidase antibodies may identify a subset of patients with distinct clinical or prognostic features.

Glomerular podocytic injury in protein overload proteinuria.

Injection of rats with large doses of bovine serum albumin causes proteinuria which may persist long after the period of overload has ended. In order to assess in this model of proteinuria the relative importance of podocytic epithelial changes versus alterations in anionic groups in the glomerular capillary wall a morphological study has been made of animals in which the kidneys were fixed by vascular perfusion or by in situ drip fixation. By transmission electron microscopy, podocytes showed protein droplets, cytoplasmic vacuoles, spreading of epithelial cytoplasm with loss of foot processes, and focal separation of epithelium from the glomerular basement membrane, occasionally with cytoplasmic disruption. Staining with colloidal iron showed no reduction in the density of anionic groups per unit area on epithelial cell surfaces or elsewhere in glomeruli. However, the reduced surface area of epithelial cells caused by the changes to their structure accounts adequately for the less intense glomerular colloidal iron staining evident by light microscopy. Changes in podocyte structure, particularly those leading to focal cytoplasmic defects on the outer surface of the glomerular basement membrane, appear to be more important than loss of glomerular anionic groups for the development of proteinuria in protein overload nephropathy.

Anti-neutrophil cytoplasmic antibodies (ANCA): their detection and significance: report from workshops.

Anti-neutrophil cytoplasmic antibodies (ANCA) are antibodies directed against enzymes that are found mainly within the azurophil or primary granules of neutrophils. There are 3 types of ANCA that can be distinguished by the patterns they produce by indirect immunofluorescence when tested on normal ethanol-fixed neutrophils. Diffuse fine granular cytoplasmic fluorescence (cANCA) is typically found in Wegener's granulomatosis, in some cases of microscopic polyarteritis and Churg Strauss syndrome, and in some cases of crescentic and segmental necrotising glomerulonephritis, but it is rare in other conditions. The target antigen is usually proteinase 3. Perinuclear fluorescence (pANCA) is found in many cases of microscopic polyarteritis and in other cases of crescentic and segmental necrotising glomerulonephritis. These antibodies are often directed against myeloperoxidase but other targets include elastase, cathepsin G, lactoferrin, lysozyme and beta-glucuronidase. The third group designated "atypical" ANCA includes neutrophil nuclear fluorescence and some unusual cytoplasmic patterns, and while a few of the target antigens are shared with pANCA, the others have not been identified. Sera that produce a pANCA or atypical ANCA pattern on alcohol-fixed neutrophils result in cytoplasmic fluorescence when formalin acetone fixation is used. pANCA or atypical ANCA occur in about 2/3 of all individuals with ulcerative colitis or primary sclerosing cholangitis, and they are found in a third of patients with Crohn's disease. The reported incidence of ANCA in rheumatoid arthritis and SLE varies considerably but the patterns are predominantly pANCA and atypical ANCA.(ABSTRACT TRUNCATED AT 250 WORDS)

Localization of terminal complement components S-protein and SP-40,40 in renal biopsies.

The terminal complement complex has been implicated in the development of glomerular injury in both experimental and, indirectly, in human glomerulonephritis. Recent data suggests that the terminal complement complex in human glomerulonephritis may be in the cytolytically inactive SC5b-9 form which also contains S-protein and a recently identified protein, SP-40,40. In this study renal biopsies were examined by immunofluorescence to determine the incidence and inter-relation of deposition of the SC5b-9 components C6, C9, S-protein and SP-40,40. All components of SC5b-9 were found in arteries and arterioles, along the tubular basement membrane and in areas of glomerulosclerosis in all biopsies. This deposition was sometimes associated with C3 but never immunoglobulin deposition and correlated with the degree of renal injury. In addition, in biopsies with glomerular deposition of immunoglobulin and C3, the SC5b-9, components co-localized with the immune deposits. Glomeruli without immune deposits or glomerulosclerosis contained none of the SC5b-9 components. The incidence and pattern of distribution of SP-40,40 was similar to that of S-protein, C6 and C9 in all of cases. These data confirm that the terminal complement complex in the kidney is, at least partly, in the SC5b-9 form both in the specific immune glomerular deposition and in the "non-specific" deposition in areas of renal injury. SP-40,40 is also found in the SC5b-9 complex in all forms of renal disease.