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Background Increased understanding of whether individuals who have recovered from COVID-19 are protected from future SARS-CoV-2 infection is an urgent requirement. We aimed to investigate whether antibodies against SARS-CoV-2 were associated with a decreased risk of symptomatic and asymptomatic reinfection. Methods A large, multicentre, prospective cohort study was done, with participants recruited from publicly funded hospitals in all regions of England. All health-care workers, support staff, and administrative staff working at hospitals who could remain engaged in follow-up for 12 months were eligible to join The SARS-CoV-2 Immunity and Reinfection Evaluation study. Participants were excluded if they had no PCR tests after enrolment, enrolled after Dec 31, 2020, or had insufficient PCR and antibody data for cohort assignment. Participants attended regular SARS-CoV-2 PCR and antibody testing (every 2–4 weeks) and completed questionnaires every 2 weeks on symptoms and exposures. At enrolment, participants were assigned to either the positive cohort (antibody positive, or previous positive PCR or antibody test) or negative cohort (antibody negative, no previous positive PCR or antibody test). The primary outcome was a reinfection in the positive cohort or a primary infection in the negative cohort, determined by PCR tests. Potential reinfections were clinically reviewed and classified according to case definitions (confirmed, probable, or possible) and symptom-status, depending on the hierarchy of evidence. Primary infections in the negative cohort were defined as a first positive PCR test and seroconversions were excluded when not associated with a positive PCR test. A proportional hazards frailty model using a Poisson distribution was used to estimate incidence rate ratios (IRR) to compare infection rates in the two cohorts. Findings From June 18, 2020, to Dec 31, 2020, 30 625 participants were enrolled into the study. 51 participants withdrew from the study, 4913 were excluded, and 25 661 participants (with linked data on antibody and PCR testing) were included in the analysis. Data were extracted from all sources on Feb 5, 2021, and include data up to and including Jan 11, 2021. 155 infections were detected in the baseline positive cohort of 8278 participants, collectively contributing 2 047 113 person-days of follow-up. This compares with 1704 new PCR positive infections in the negative cohort of 17 383 participants, contributing 2 971 436 person-days of follow-up. The incidence density was 7·6 reinfections per 100 000 person-days in the positive cohort, compared with 57·3 primary infections per 100 000 person-days in the negative cohort, between June, 2020, and January, 2021. The adjusted IRR was 0·159 for all reinfections (95% CI 0·13–0·19) compared with PCR-confirmed primary infections. The median interval between primary infection and reinfection was more than 200 days. Interpretation A previous history of SARS-CoV-2 infection was associated with an 84% lower risk of infection, with median protective effect observed 7 months following primary infection. This time period is the minimum probable effect because seroconversions were not included. This study shows that previous infection with SARS-CoV-2 induces effective immunity to future infections in most individuals. Funding Department of Health and Social Care of the UK Government, Public Health England, The National Institute for Health Research, with contributions from the Scottish, Welsh and Northern Irish governments.

Summary Background BNT162b2 mRNA and ChAdOx1 nCOV-19 adenoviral vector vaccines have been rapidly rolled out in the UK from December, 2020. We aimed to determine the factors associated with vaccine coverage for both vaccines and documented the vaccine effectiveness of the BNT162b2 mRNA vaccine in a cohort of health-care workers undergoing regular asymptomatic testing. Methods The SIREN study is a prospective cohort study among staff (aged ≥18 years) working in publicly-funded hospitals in the UK. Participants were assigned into either the positive cohort (antibody positive or history of infection [indicated by previous positivity of antibody or PCR tests]) or the negative cohort (antibody negative with no previous positive test) at the beginning of the follow-up period. Baseline risk factors were collected at enrolment, symptom status was collected every 2 weeks, and vaccination status was collected through linkage to the National Immunisations Management System and questionnaires. Participants had fortnightly asymptomatic SARS-CoV-2 PCR testing and monthly antibody testing, and all tests (including symptomatic testing) outside SIREN were captured. Data cutoff for this analysis was Feb 5, 2021. The follow-up period was Dec 7, 2020, to Feb 5, 2021. The primary outcomes were vaccinated participants (binary ever vacinated variable; indicated by at least one vaccine dose recorded by at least one of the two vaccination data sources) for the vaccine coverage analysis and SARS-CoV-2 infection confirmed by a PCR test for the vaccine effectiveness analysis. We did a mixed-effect logistic regression analysis to identify factors associated with vaccine coverage. We used a piecewise exponential hazard mixed-effects model (shared frailty-type model) using a Poisson distribution to calculate hazard ratios to compare time-to-infection in unvaccinated and vaccinated participants and estimate the impact of the BNT162b2 vaccine on all PCR-positive infections (asymptomatic and symptomatic). This study is registered with ISRCTN, number ISRCTN11041050, and is ongoing. Findings 23 324 participants from 104 sites (all in England) met the inclusion criteria for this analysis and were enrolled. Included participants had a median age of 46·1 years (IQR 36·0–54·1) and 19 692 (84%) were female; 8203 (35%) were assigned to the positive cohort at the start of the analysis period, and 15 121 (65%) assigned to the negative cohort. Total follow-up time was 2 calendar months and 1 106 905 person-days (396 318 vaccinated and 710 587 unvaccinated). Vaccine coverage was 89% on Feb 5, 2021, 94% of whom had BNT162b2 vaccine. Significantly lower coverage was associated with previous infection, gender, age, ethnicity, job role, and Index of Multiple Deprivation score. During follow-up, there were 977 new infections in the unvaccinated cohort, an incidence density of 14 infections per 10 000 person-days; the vaccinated cohort had 71 new infections 21 days or more after their first dose (incidence density of eight infections per 10 000 person-days) and nine infections 7 days after the second dose (incidence density four infections per 10 000 person-days). In the unvaccinated cohort, 543 (56%) participants had typical COVID-19 symptoms and 140 (14%) were asymptomatic on or 14 days before their PCR positive test date, compared with 29 (36%) with typical COVID-19 symptoms and 15 (19%) asymptomatic in the vaccinated cohort. A single dose of BNT162b2 vaccine showed vaccine effectiveness of 70% (95% CI 55–85) 21 days after first dose and 85% (74–96) 7 days after two doses in the study population. Interpretation Our findings show that the BNT162b2 vaccine can prevent both symptomatic and asymptomatic infection in working-age adults. This cohort was vaccinated when the dominant variant in circulation was B1.1.7 and shows effectiveness against this variant. Funding Public Health England, UK Department of Health and Social Care, and the National Institute for Health Research.

Objectives To determine the accuracy of using fellow-eye biometry for intraocular lens calculations for phacovitrectomy for macula off rhegmatogenous retinal detachments. Methods Retrospective case review of phacovitrectomies for consecutive macula off retinal detachments over 10 years. Optical and/or ultrasound biometry was performed for affected and fellow eyes. Prediction error was determined by calculating the difference between predicted and actual refractive outcomes. Results from fellow- and same-eye biometry were compared. Results Forty-two eyes were included. The mean prediction errors for fellow- and same-eye biometry were -0.01 ± 1.09 and -1.22 ± 2.32 dioptres, respectively, indicating a myopic shift for same eye biometry calculations. The mean absolute prediction errors for fellow and same eye biometry were 0.73 ± 0.80 and 1.57 ± 2.08 dioptres, respectively. The difference was statistically significant (P = 0.016). Conclusions When appropriate, intraocular lens calculations using fellow-eye biometry for phacovitrectomy for macula off rhegmatogenous retinal detachments are accurate and better than those from same-eye biometry.

Highlights • COVID-19 has significant impact on PD research and education activities. • Country-specific restrictions may pose challenges to PD research and require careful adaptations. • Neurological Symptoms of COVID-19 may overlap with PD.

Parkinson's disease (PD) is an incurable, progressive neurological condition, with symptoms impacting movement, walking, and posture that eventually become severely disabling. Advanced PD (aPD) has a significant impact on quality-of-life (QoL) for patients and their caregivers/families. Levodopa/carbidopa intestinal gel (LCIG) is indicated for the treatment of advanced levodopa-responsive PD with severe motor fluctuations and hyper-/dyskinesia when available combinations of therapy have not given satisfactory results.To determine the cost-effectiveness of LCIG vs standard of care (SoC) for the treatment of aPD patients.A Markov model was used to evaluate LCIG vs SoC in a hypothetical cohort of 100 aPD patients with severe motor fluctuations from an Irish healthcare perspective. Model health states were defined by HoehnYahr (HY) scale-combined with amount of time in OFF-time-and death. SoC comprised of standard oral therapy ± subcutaneous apomorphine infusion and standard follow-up visits. Clinical efficacy, utilities, and transition probabilities were derived from published studies. Resource use was estimated from individual patient-level data from Adelphi 2012 UK dataset, using Irish costs, where possible. Time horizon was 20 years. Costs and outcomes were discounted at 4%. Both one-way and probabilistic sensitivity analyses were conducted.The incremental cost-effectiveness ratio for LCIG vs SOC was €26,944/quality adjusted life year (QALY) (total costs and QALYs for LCIG vs SoC: €537,687 vs €514,037 and 4.37 vs 3.49, respectively). LCIG is cost-effective at a payer threshold of €45,000. The model was most sensitive to health state costs.LCIG is a cost-effective treatment option compared with SoC in patients with aPD.

Background There is a growing use of electronic databases for asthma studies, many of which use exacerbations to assess asthma control, severity and determine eligibility for biologic treatment.1 Databases identify severe exacerbations based on prednisolone prescriptions, however its accuracy in counting exacerbations is not validated. We determined whether healthcare databases accurately identify asthma exacerbation numbers and the true proportion of UK primary care patients eligible for treatment with mepolizumab. Methods Demographic and treatment information were collected from adults with asthma from ten UK general practices over a 12 months period. Frequent exacerbators (FE) were defined as ≥2 exacerbations in the past year. Oral corticosteroid (OCS) prescriptions were manually checked against clinical records for FE identified by database search. Prescriptions for non-asthma indications, dose Results Of 2639 patients with active asthma, 254 (10%) FE were identified using electronic database searches. Whereas 185 (7%) FE were confirmed after manually reviewing OCS prescriptions. Database search overestimated FE by 37% and has a positive predictive value of 73%. Of 1000 prescriptions examined from eight practices, 302 (30%) prescriptions were discounted as an asthma exacerbation. The most common reason for overcounting of exacerbations was consecutive prescriptions given within 7 days. Less common reasons included OCS prescribed for other conditions, low dose maintenance OCS or emergency supply prescriptions. 30 patients had ≥4 exacerbations in the past year and/or were on maintenance OCS dose ≥5mg daily. 22 (73%) had BEC recorded in the past year. Twelve patients were eligible for mepolizumab according to NICE criteria. Conclusion Primary care electronic database searches overestimated FE by 37%. Accuracy can be improved by adding the date, indication and daily dose of OCS in the search algorithm. Using confirmed exacerbation numbers and applying blood eosinophil criteria where available, 0.5% of patients with active asthma attending primary care in an urban area could be considered for mepolizumab. References Kerkhof, et al. Thorax 2018;73:116–124.

In this paper, the user requirements, along with the methodology adopted towards their identification within the i-PROGNOSIS framework (www.i-prognosis.eu), are presented. The latter are placed within the concept of active and healthy ageing (AHA), focusing on the case of Parkinson's Disease (PD) patients' support. The bases for the user requirements identification were face-to-face sessions, focus groups and a large scale Web-survey. Towards the efficient user requirements identification and i-PROGNOSIS components development, exemplified usage scenarios and related business processes the stakeholders of i-PROGNOSIS can perform, are discussed. Overall, 122 functional and non-functional requirements were identified, serving as a basis for the spiral development model of i-PROGNOSIS, revealing the beneficial role of the users in designing solutions within the AHA concept.

Aging is associated with a decline in peripheral nerve function of both motor and sensory nerves. The decline in function of peripheral sensorimotor nerves with aging has been linked to sarcopenia, the age-related decline in muscle mass and function that significantly compromises the quality of life in older humans. In this study, we report a significant increase in oxidized fatty acids and insoluble protein carbonyls in sciatic nerves of aged C57BL/6 male mice (28-30mo) that exhibit a profound decline in motor nerve function and degenerative changes in both axon and myelin structure, compared to young mice (6-8mo). Our data further suggests that this age-related loss of function of peripheral motor nerves is likely precipitated by changes in mechanisms that protect and/or repair oxidative damage. We predict that interventions that target these mechanisms may protect against age-related decline in peripheral sensorimotor nerve function and likely improve the debilitating outcome of sarcopenia in older humans.

Physicians and surgeons rely on subtle tissue changes to detect the extent of tumors and the presence of residual disease in the clinical setting. The development of a cancer-specific fluorescent contrast agent has the potential to provide real-time tumor imaging in the clinic or operating room. Because epidermal growth factor receptor (EGFR) is highly overexpressed on the surface of head and neck squamous cell carcinoma (HNSCC), we sought to determine if fluorescently labeled anti-EGFR antibody could be used to image HNSCC xenografts in vivo. Cetuximab or control isotype-matched IgG1 was conjugated with the Cy5.5 fluorochrome and systemically injected into mice bearing human split thickness skin grafts, tumor cell line xenografts, transplanted human tumor xenografts, or mouse mesothelioma tumors. Xenografts were imaged by time-domain fluorescence imaging or fluorescence stereomicroscopy. Both imaging modalities detected specific uptake of cetuximab-Cy5.5 in HNSCC xenografts with significantly higher fluorescence levels relative to control IgG1-Cy5.5. Tumor xenograft fluorescence was higher compared with background (before injection), human split thickness skin grafts, or mouse mesothelioma tumors at 24, 48, and 72 h. Fluorescence was detected in multiple HNSCC tumor cell lines with variable EGFR expression levels. Mock resections of flank tumors using fluorescence stereomicroscopy showed that small (2 mm) specimens could be detected in the surgical wound bed. These results show the feasibility of using fluorescently labeled anti-EGFR antibody to detect human tumors in the surgical setting. [Mol Cancer Ther 2007;6(4):1230–8]

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disease characterized by degeneration and death of motor neurons. Aberrant protein aggregation and oxidative stress are implicated in the etiology of ALS; thus preventing propagation of early aggregation events and oxidative damage could be an effective therapy. We tested the effect of dietary supplementation (initiated 40 days of age) with 2-(2-hydroxyphenyl)-benzoxazole (HBX), a compound with metal chelator and anti-aggregation properties, on disease onset, progression and lifespan in the G93A mouse model of ALS. Tests were not sufficiently powerful to detect any change to survival distribution of mice treated with HBX. However, the disease onset was delayed and max lifespan was increased in the treatment group. Additionally, disease progression was moderated as shown by reduced neuromuscular denervation measured by repetitive nerve stimulation. F2-isoprostanes, a marker of oxidative damage, are elevated in skeletal muscle from G93A mice at onset and this increase is prevented in HBX fed G93A mice. Furthermore, HBX treatment reduced mutant SOD1 protein aggregation in whole spinal cord of G93A mice at disease onset. Overall, our data suggests that HBX may be able to improve the degenerative symptoms of ALS through the prevention of oxidative damage and protein aggregation. Further studies are needed to uncover the mechanistic effects of HBX in ameliorating ALS pathology.

Restless legs syndrome (RLS), also known as Ekbom syndrome, is a common movement disorder with sensorimotor symptoms occurring during sleep and quiet wakefulness. The underlying cause for RLS is unknown but genetic influences play a strong part in the pathogenesis of RLS, particularly when the condition starts at a young age. This review explores the genetic basis of RLS and related phenotypic variations. Recently, three loci showing vulnerability to RLS have been described in French-Canadian and Italian families in chromosomes 12q, 14q and 9q, emphasising on an autosomal dominant mode of inheritance. These have been labelled RLS1, RLS2 and RLS3, respectively. However, specific causative mutations remain elusive and no linkage analysis has been identified so far in the candidate genes investigated in RLS.

Elevated homocysteine level is an independent risk factor for ischemic stroke, thrombotic and cardiovascular diseases. The enzyme methylenetetrahydrofolate reductase (MTHFR) plays a crucial role in regulating the levels of homocysteine. A C677T mutation in this gene results in reduced activity. Sixty-nine patients with arterial stroke, six patients with venous stroke (confirmed by computed tomography and/or magnetic resonance imaging) with hyperhomocysteinemia were selected for the study. Forty-nine subjects with no past history of stroke served as controls. MTHFR genotypes were determined by PCR using specific primers, followed by restriction digestion and gel analysis. The prevalence of the mutated homozygous and heterozygous C677T MTHFR genotype in the patients with arterial stroke was 1.4% (one of 69) and 31.88% (21 of 69), respectively. There frequency was 16.6% (one of six) and 33.3% (two of six) in venous stroke. The genotyping results from controls showed that there was only one heterozygote out of the 49 studied (2.08%). There was a significant difference between the control and the patient groups. Odds ratio for the probability of the C677T MTHFR gene mutation in the patients versus control group was 22.29 (95% CI 4.89-98.8). This indicates that C677T MTHFR mutation is strongly associated with arterial stroke especially in young adults. MTHFR allele evaluation will help in preventing/reducing morbidity caused by stroke.

An approach to image radiolabeled peptide localization at tumor sites by inducing tumor cells to synthesize membrane expressed human somatostatin receptor subtype 2 (hSSTr2) with a high affinity for radiolabeled somatostatin analogues is described. The use of gene transfer technology to induce expression of high affinity membrane hSSTr2 can enhance the specificity and degree of radiolabeled peptide localization in tumors. Employing this strategy, induction of high levels of hSSTr2 expression with selective tumor uptake of radiolabeled peptides was achieved in both subcutaneous non-small cell lung cancer and intraperitoneal ovarian cancer mouse human tumor xenograft models. The features of this genetic transduction imaging approach are: (1) constitutive expression of a tumor-associated receptor is not required; (2) tumor cells are altered to express a new target receptor or increased quantities of a constitutive receptor at levels which may significantly increase tumor targeting of radiolabeled peptides compared to uptake in normal tissues; (3) gene transfer can be accomplished by local or regional injection of adenoviral vectors; (4) it is feasible to target adenovirus vectors to tumor cells by modifying adenoviral tropism (binding) or by the use of tumor-specific promoters such that the hSSTr2 will be specifically expressed in the desired tumor; and (5) this technique can be used to image expression of a second therapeutic gene.

Background. Acidic fibroblast growth factor (FGF-1) functions as a potent hormonal inducer of wound repair mechanisms in vivo. In addition, the involvement of FGF-1 in a number of pathophysiological conditions, including chronic human renal allograft rejection, has been described. Consequently, there is an increasing need to monitor FGF-1 pharmacokinetics and distribution for both therapeutic and diagnostic opportunities. We now describe in vivo imaging and targeting of FGF-1 in renal transplanted rats. Methods. Sham-operated, syngeneic renal transplanted, and allogeneic renal transplanted rats were imaged using an Anger gamma camera. Renal function was evaluated first by dynamic 99m Tc-MAG 3 imaging, and subsequently, 99m Tc-labeled FGF-1 ( 99m Tc-FGF-1) was imaged after i.v. injection. Microautoradiography of harvested kidneys determined the compartmental localization of 99m Tc-FGF-1. Results. 99m Tc-MAG 3 renal scans were grossly abnormal in the allogeneic renal transplanted rats. In this group, a significant reduction in 99m Tc-FGF-1 renal binding was measured by imaging analyses, as compared with renal binding in the sham-operated and syngeneic renal transplanted groups, which were not significantly different. Both groups of renal transplanted rats showed a redistribution of FGF-1 to the glomerular compartment. Conclusions. 9m Tc-FGF-1 serves as a new radiotracer to measure in vivo targeting of the growth factor. Reduced renal binding of 99m Tc-FGF-1 in the allogeneic transplanted kidney was consistent with decreased blood flow. Unique glomerular targeting of 99m Tc-FGF-1 in the transplanted kidney provides additional evidence supporting a role for this growth factor in the pathogenesis of chronic rejection.

Little is known about risk factors for complications of Escherichia coli O157:H7 infection in adults. The 1996 outbreak in central Scotland involved the largest number of adult case patients in whom hemolytic uremic syndrome (HUS) developed and, ultimately, the largest number of deaths associated with E. coli O157:H7 infection that has yet been recorded. We investigated risk factors for HUS in a retrospective study of all hospitalized case patients in this outbreak. Of 120 case patients, 34 had HUS develop, 28 of whom were adults. Sixteen adults died. Significant risk factors for HUS were age15 years or65 years (odds ratio [OR], 4.4; 95% confidence interval [CI], 1.3-14.4), hypochlorhydria (OR, 6.7; 95% CI, 1.9-24.0), and coincidental antibiotics (OR, 4.7; 95% CI 1.4-16.5). Factors associated with HUS were as follows: white blood cell count20 x 10(9) cells/L (OR, 8.25; 95% CI, 1.1-60.3), neutrophil count15 x 10(9) cells/L (OR, 8.5; 95% CI, 1.5-50.1), and serum albumin level35 g/L (OR, 7.2; 95% CI, 1.2-42.5)or =3 days after symptom onset. Deaths were confined to case patients65 years of age. Early identification of risk factors for HUS is vital and could select case patients for trials of preventative and treatment therapies.

Recombinant human acidic fibroblast growth factor (FGF-1) was radiolabeled with 99mTc by the HYNIC method. The 99mTc-FGF-1 retained its representative molecular mass, heparin affinity, cellular binding to both low (Kd = 9.5 nM) and high (Kd = 125 pM) affinity sites, and mitogenic activity. Gamma camera imaging after intravenous dosing in rats confirmed high liver and kidney binding. Heparin significantly decreased 99mTc-FGF-1 liver uptake and increased urinary excretion. These studies illustrate a new method for imaging FGF-1 targeting under various conditions.

Objective To determine the potential of an E-selectin–binding peptide (ESbp) to specifically bind activated endothelium in rheumatoid arthritis (RA) animal models. Methods ESbp (KYDGDITWDQLWDLMK; 2,027 daltons) was labeled with biotin and 99mTc. The affinity of ESbp derivatives for E-selectin was measured by enzyme-linked immunosorbent assay. The binding of biotin-ESbp was compared with that of an anti–E-selectin antibody, by immunohistochemical analyses of human synovial sections and sections from the Mycoplasma pulmonis MRL-lpr/lpr mouse arthritis model. 99mTc-ESbp was sequentially imaged in vivo with a gamma camera in the rat adjuvant-induced arthritis model. Results E-selectin expression was detected in human RA synovium and mouse arthritic synovium using biotin-ESbp. Both biotin-ESbp and 99mTc-labeled ESbp had high affinity for E-selectin (dissociation constant 2–5 nM). In vivo imaging showed specific binding of 99mTc-ESbp to the rat ankle joint prior to clinical manifestations of inflammation. Conclusion These results demonstrate that activated endothelium can be targeted with 99mTc-ESbp. The specificity of targeting can be used to evaluate up-regulation of E-selectin in RA models, and to follow changes in this up-regulation during treatment trials.

A study was undertaken to identify the variation of entrance skin doses (ESDs) in mobile neonatal chest radiography with regard to the European Commission (EC) reference dose and to examine potential relationships with image quality and radiographic techniques. Five sites from the former North West Thames region participated. All mobile neonatal radiographic techniques were surveyed. Dose-area product per examination was directly measured and the ESD calculated. Image quality criteria were developed from those published by the EC. Image quality was graded by two independent observers. Over the five sites, 144 examinations were recorded. Calculated ESDs ranged up to 160 microGy, with an appreciable variation not only between sites but also within sites. A clear relationship between actual rather than nominal speed and dose over all sites was demonstrated (r = -0.95, p = 0.013). No correlation between image quality and dose was noted (r = -0.044, p = 0.665). Neonatal imaging systems at participating sites, within the North Thames region, comply with EC guidelines on patient dose and image quality for mobile chest X-rays. Significant variation in ESDs was encountered between sites with no discernible relationship with image quality or the employed radiographic techniques as described by the EC. The strong inverse relationship between ESDs and actual rather than nominal speed suggests a neglected aspect of radiation protection.

Non-traumatic sixth nerve palsy in the 20-50 years old group is unusual and a detailed history is often needed to identify serious and potentially reversible causes. We present a case of sixth sense nerve palsy in a young female with eczema for which she was treated with low-dose cyclosporin. We review the indications for and ocular side effects of cyclosporin, a drug with which most ophthalmologists will be unfamiliar.

In October 1990 there was a severe outbreak of Escherichia coli O157 in two psychogeriatric wards of a large psychiatric hospital in Lanarkshire. There were 11 cases (eight patients and three staff), of whom four died (all patients). Two cases, one staff and one patient (the likely index case) were identified serologically after the outbreak was over. E. coli O157 was not cultured from any food, water or milk samples, and the evidence suggests that the index case had eaten food brought into the hospital. The results also suggest that the incubation period of the organism may be longer than is currently recognized, particularly for person-to-person spread. A Fatal Accident Inquiry was held into the deaths, and the Sheriff's Determination is discussed together with the implications of the results for infection control procedures.

Background. Positron emission tomography offers advantages for radioimmunodiagnosis of cancer but requires radionuclides of appropriate half-life that have high specific activity and high radio-purity. This work was designed to develop a viable method to produce and purify 64 Cu, which has high specific activity, for positron emission tomography. Methods. 64 Cu was produced at the University of Missouri Research Reactor by the nuclear reaction, 64 Zn(n,p) 64 Cu. Highly pure zinc metal (99.9999%) was irradiated in a specially designed boron nitride lined container, which minimized thermal neutron reactions during irradiation. A new two-step procedure was developed to chemically separate the no-carrier-added 64 Cu from the zinc metal target

Background. Murine monoclonal antibodies (MoAb) potentially can be used in the radioimmunodetection and radioimmunotherapy of cancer. However, the administration of these radiopharmaceuticals to humans often leads to induction of human anti-murine antibodies (HAMA). HAMA has many disadvantages, which could decrease efficacy of the murine MoAb. The purpose of this work was to produce human monoclonal antibody against a human ovarian cancer cell surface antigen (OCCSA), which was not present in normal ovarian cells. This 200-kilodalton OCCSA also was used in the present study for characterizing the human monoclonal antibody

Background. There is no reliable method for the early diagnosis of ovarian cancer. Radiolabeled monoclonal antibodies have potential to assist in early diagnosis, but they are limited by problems that include antibody specificity, stability, and immunoreactivity, as well as patient reactions to the antibodies used. Methods. Methods were developed to 198 Au-label a human monoclonal antibody (TC5 antibody), developed against an ovarian cancer cell surface antigen. Antigen binding sites on the TC5 antibody were protected with sepharose 4B affinity chromatography before 198 Au-labeling

We have studied beta-adrenoceptor number and affinity on peripheral blood mononuclear cells (PBMCs) in normotensives (NT) and hypertensives (HT), before and after intravenous administration of clonidine, an alpha 2-adrenoceptor agonist which lowers blood pressure predominantly by reducing central nervous system sympathetic outflow. After clonidine, there was a decrease in blood pressure and plasma noradrenaline (NA) and adrenaline (Ad) levels, with an increase in growth hormone (GH) levels, in both NT and HT. There was no difference in basal beta-adrenoceptor densities on PBMCs between NT and HT. After clonidine at 30 and 60 min, there was an increase in beta-adrenoceptor density associated with a low affinity in NT. In HT, no changes were observed. The increased beta-adrenoceptor densities on PBMCs in NT after clonidine, returned to baseline values after 2 h. Short term up-regulation of beta-adrenoceptors on PBMCs in NT after clonidine is accompanied by a fall in blood pressure (BP) and plasma levels of catecholamines. The changes may represent a compensatory mechanism reflecting a rapid externalization-activation of adrenoceptors residing on the internal surface of the membranes with a change of the coupling ability between the receptor and the catalytic component. In HT, although the haemodynamic and neurohormonal response to clonidine was similar to NT, short term upregulation of receptors did not occur. The lack of such response may mirror a form of regulatory dysfunction of beta-adrenoceptors in HT.

1. The cardiovascular effects of oral alcohol (0.5 g/kg body weight diluted to 300 ml in sugar-free orange juice) were compared with those of placebo in 10 normal subjects. Measurements were made while the subjects were supine and horizontal for 45 min and after 10 min of 45° head-up tilt. 2. After alcohol, plasma alcohol levels rose from 1.9 ± 1.3 to 61.6 ± 6.5 mg/100 ml. After placebo, plasma alcohol levels did not increase. After alcohol and placebo, supine blood pressure was unchanged; heart rate, both supine and during tilt, rose after alcohol only. 3. After alcohol, superior mesenteric artery and digital skin blood flow increased and calculated vascular resistances fell. There was no change after placebo. 4. Forearm blood flow, forearm vascular resistance and cardiac index did not change in either phase, except for a fall in cardiac index during tilt but only after alcohol. 5. In conclusion, the acute ingestion of 0.5 g of alcohol/kg body weight in normal subjects raised heart rate and actively dilated the superior mesenteric artery and digital skin vessels. There was no effect on blood pressure, cardiac output and skeletal muscle vascular tone. During head-up tilt after alcohol, there was a tendency for blood pressure to fall with a compensatory rise in heart rate.

In this paper, a theoretical model is proposed to estimate the resonant frequency of a circular split ring resonator (C-SRR) in which the outer ring is rotated. The variation in the resonant frequency with angle of rotation of the SRR is theoretically calculated. The computed values are then compared with the simulated results using an electromagnetic simulator. Also, the magnetic polarizability for different angle of rotation is extracted from the simulated data.

To assess the visual outcome of eyes undergoing Artisan lens implantation for aphakia, to identify reasons for poor outcomes, and to report incidences of post-operative uveitis, glaucoma, or hyphaema. A retrospective analysis of 32 eyes rendered aphakic through various causes, which subsequently underwent Artisan lens implantation. A total of 32 eyes from 31 patients were reviewed. Follow-up ranged from 6 to 42 months, mean 17.3 months. The commonest cause of aphakia was following complicated phacoemulsification in 17 of the 32 eyes (53.1%). At final follow-up, 21 of the 32 eyes (65.6%) achieved best-corrected visual acuity (BCVA) better than that measured pre-operatively and 10 of the 32 eyes (31.3%) matched their pre-operative BCVA. Of 33 eyes, only 1 (0.03%) attained a final BCVA worse than pre-operatively, owing to non-arteritic anterior ischaemic optic neuropathy. A total of 4 of the 33 eyes (12.5%) had pre-existing glaucoma or ocular hypertension; no additional intraocular pressure problems were identified during the follow-up period. This study suggests that Artisan iris claw lens insertion is beneficial in acquired aphakia, matching or exceeding pre-operative BCVA in the overwhelming majority of the cases. In addition, this series did not identify any post-operative problems with uveitis, glaucoma, or hyphaema.

The object of this study was to determine the efficiency of the short tau inversion recovery (STIR) sequence in the assessment of salivary disease. Sixteen patients with tumours either in or adjacent to the parotid gland were imaged using a 1.5T Philips Gyroscan, with a standard head coil. T1-weighted spin-echo and STIR sequences were obtained in multiple planes and assessed independently by each of the authors. Positive fine needle aspiration cytology or histological proof of the nature of the imaged lesions was obtained for every patient. T1-weighted spin-echo images were most useful for visualizing anatomical structures and for identification of the facial nerve. All lesions were visible with T1-wcighted images but were very much more conspicuous in the STIR sequences, for which a minimal lesion resolution of 6 mm was achieved. No contrast enhancement was required. It was not possible to determine the pathological nature of the lesion by scan appearance only. Our conclusion is that a combination of T1-weighted spin-echo and STIR sequences in the axial and coronal planes is the preferred protocol for salivary gland imaging.

xBASE is a genome database aimed at helping laboratory-based bacteriologists make best use of bacterial genome sequence data, with a particular emphasis on comparative genomics. The latest version, xBASE 2.0 (http://xbase.bham.ac.uk), now provides comprehensive coverage of all bacterial genomes and features an updated modularized backend and an improved user interface, which includes a taxonomy browser and a powerful full-text search facility.

Phlebography is frequently requested to confirm or exclude deep venous thrombosis in patients presenting with a painful, swollen calf or leg. We have noted a small proportion of those with negative phlebograms to have compression or lateral deviation of the popliteal vein. These patients were submitted to contrast arthrography. Eighty per cent of this selected group were found to have dissecting or ruptured Baker's cysts; almost a third of these were dissections upwards into the thigh. A positive diagnosis in these patients is important as management differs from deep vein thrombosis. The optimum diagnostic strategy in patients with a swollen, painful leg is firstly to perform ultrasound of the femoral vein and popliteal fossa to exclude obvious thrombus or ruptured Baker's cyst. If this examination is negative, or a Baker's cyst is shown with no evidence of rupture, phlebography should be performed to exclude calf vein thrombosis. If this examination is negative, but a Baker's cyst is present, or deviation or compression of the popliteal vein is detected, contrast arthrography is suggested to look for rupture of the cyst.

A murine, apoptosis-inducing monoclonal antibody (mTRA-8) targeting human DR5 was radiolabeled with Tc-99m. The binding affinity (Kd) and the number of DR5 receptors were measured in MD MBA-231–derived 2LMP cell lines that were “sensitive” or “resistant” to mTRA-8 killing. Single-photon emission computed tomography and X-ray computed tomography (SPECT/CT) evaluated the Tc-99m-mTRA-8 retention and distribution within xenograft tumors; biodistribution analyses confirmed the levels. Scatchard assays showed specific and high binding affinity of Tc-99m-mTRA-8 to DR5; the killing efficacy of mTRA-8 was unchanged by Tc-99m labeling. There was no significant difference between sensitive and resistant 2LMP cells for Kd values (1.5 ± 0.3 nmol/L = acid labile), or DR5 receptors (mean/cell = 11,000). SPECT/CT imaging analyses at 6 h after injection of Tc-99m-mTRA-8 revealed the second 1.5 mm shell from the surface of the mammary fat pad tumors (n = 5; 5,627 mm3) retained 12.7 ± 1.4%ID/g, higher than the other shells, with no difference between the sensitive and resistant 2LMP tumors. Binding of Tc-99m–labeled mTRA-8 in tumor was specific; excess unlabeled mTRA-8 blocked Tc-99m-mTRA-8 retention in tumor by 45%. Retention of Tc-99m–labeled isotype antibody in tumor was consistent with the blocking study, and 30% lower. These studies show that SPECT/CT imaging provided detailed distribution information of Tc-99m–labeled mTRA-8 within breast tumor xenografts. Imaging could provide a mechanism to assess DR5 modulation when DR5 therapy is combined with chemotherapy and radiation, and thereby aid in optimizing the dosing schedule. [Mol Cancer Ther 2007;6(3):866–75]

We report the case of an unusual presentation of myasthenia gravis with tongue atrophy and fasciculation. Myasthenia gravis is an autoimmune condition associated with weakness and fatigability of voluntary muscles. In >50%, the initial symptoms and signs are related to extraocular muscle weakness, such as diplopia or ptosis [Tsung K, Seggev JS. An unusual cause of dysphagia. West J Med 1995; 163: 159-60]. Rarely, it is known to affect bulbar muscles and can lead to dysphagia and respiratory compromise.

The skeletal changes of untreated thalassaemia result from ineffective erythropoiesis and expansion of the bone marrow and affect every part of the skeleton. These changes include osteoporosis, growth retardation, platyspondyly and kyphosis. Erythropoiesis occurs at extra-medullary sites, most commonly resulting in a paraspinal mass but occasionally affecting organs containing pluripotential stem cells. Repeated transfusion unaccompanied by iron chelation causes haemosiderosis; iron is deposited at various sites causing functional impairment. Iron-chelation therapy with desferrioxamine (DFX) prevents haemosiderosis but causes a skeletal dysplasia predominantly affecting the rapidly growing long bones, in particular the distal ulna, and causing irregularity and sclerosis of the physeal–metaphyseal junction and splaying of the metaphysis. DFX also exacerbates the observed growth retardation. DFX-induced skeletal dysplasia may herald toxicity, which is associated with visual and auditory impairment. Therefore, careful balancing of the transfusion regimen and iron-chelation therapy is required. Magnetic resonance imaging (MRI) is the most sensitive technique for the detection of DFX-induced dysplasia.

BACKGROUND IL-18 is a cytokine which is known to have an important role in the development of a Th1 lymphocyte response. As such, it may have a regulatory role in asthma by modifying Th2 lymphocyte responses. Cigarette smoking may amplify the airway inflammation associated with asthma. OBJECTIVE This study investigated if IL-18 could be detected in induced sputum from asthmatics and normal subjects and if smoking altered IL-18 levels. METHODS Induced sputum was obtained from asthmatic (31 smokers, 35 non-smokers) and normal (20 smokers, 20 non-smokers) subjects. All smokers had a smoking history of > or =15 pack years. IL-18 levels in sputum supernatant were measured by ELISA. IL-18 mRNA expression and cellular localization were assessed by quantitative PCR and immunocytochemistry, respectively. RESULTS Smoking was associated with a significant reduction in IL-18 levels (median (interquartile range) - smokers 20 (0-102) pg/mL vs. non-smokers 358 (50-876) pg/mL, P

To the best of our knowledge, this prospective study is the first to investigate the prevalence of acetabular labrum tears in athletes presenting with groin pain. Eighteen athletes who presented to our sports clinic with groin pain, underwent clinical assessment and magnetic resonance arthrography (MRa) to detect presence or absence of acetabular labrum tears. Ethical committee approval and informed consent was obtained from each patient. In four out of these eighteen athletes (22%) the MRa demonstrated the presence of acetabular labrum tear. Three of them underwent arthroscopic debridement of their acetabular labrum tears and returned to their sporting activities within 8 months. Clicking sensation of the hip was a sensitive (100%) and specific (85%) clinical symptom to predict labral tears. The internal rotation-flexion-axial compression manoeuvre was sensitive (75%) but not specific (43%). The Thomas test was neither sensitive nor specific. The conclusion of the study is that acetabular labrum tears can be a common cause of groin pain in athletes. Sports clinicians managing athletes with groin pain have to be well aware of the condition.

Objective: To determine whether combination therapy with lofepramine, L-phenylalanine, and intramuscular vitamin B-12 (the "Cari Loder regime") reduces disability in patients with multiple sclerosis. Methods: A placebo controlled, double blind, randomised study carried out in five United Kingdom centres on outpatients with clinically definite multiple sclerosis, measurable disability on Guy's neurological disability scale (GNDS), no relapse in the preceding six months, and not on antidepressant drugs. Over 24 weeks all patients received vitamin B-12, 1 mg intramuscularly weekly, and either lofepramine 70 mg and L-phenylalanine 500 mg twice daily, or matching placebo tablets. Outcome was assessed using the GNDS, the Kurtzke expanded disability status scale; the Beck depression inventory, the Chalder fatigue scale, and the Gulick MS specific symptom scale. Results: 138 patients were entered, and two were lost from each group. There was no statistically significant difference between the groups at entry or at follow up. Analysis of covariance suggested that treated patients had better outcomes on four of the five scales used. Both groups showed a reduction of 2 GNDS points within the first two weeks, and when data from all time points were considered, the treated group had a significant improvement of 0.6 GNDS points from two weeks onwards. Conclusions: Patients with multiple sclerosis improved by 2 GNDS points after starting vitamin B-12 injections. The addition of lofepramine and L-phenylalanine added a further 0.6 points benefit. More research is needed to confirm and explore the significance of this clinically small difference.

To compare two systems for assessing gene transfer to cancer cells and xenograft tumors with noninvasive gamma camera imaging.A replication-incompetent adenovirus encoding the human type 2 somatostatin receptor (hSSTr2) and the herpes simplex virus thymidine kinase (TK) enzyme (Ad-hSSTr2-TK) was constructed. A-427 human lung cancer cells were infected in vitro and mixed with uninfected cells at different ratios. A-427 tumors in nude mice (n = 23) were injected with 1 x 10(6) to 5 x 10(8) plaque-forming units (pfu) of Ad-hSSTr2-TK. The expressed hSSTr2 and TK proteins were imaged owing to internally bound, or trapped, technetium 99m ((99m)Tc)-labeled hSSTr2-binding peptide (P2045) and radioiodinated 2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl-5-iodouracil (FIAU), respectively. Iodine 125 ((125)I)-labeled FIAU was used in vitro and iodine 131 ((131)I)-labeled FIAU, in vivo. The (99m)Tc-labeled P2045 and (125)I- or (131)I-labeled FIAU were imaged simultaneously with different window settings with an Anger gamma camera. Treatment effects were tested with analysis of variance.Infected cells in culture trapped (125)I-labeled FIAU and (99m)Tc-labeled P2045; uptake correlated with the percentage of Ad-hSSTr2-TK-positive cells. For 100% of infected cells, 24% +/- 0.4 (mean +/- SD) of the added (99m)Tc-labeled P2045 was trapped, which is significantly lower (P.05) than the 40% +/- 2 of (125)I-labeled FIAU that was trapped. For the highest Ad-hSSTr2-TK tumor dose (5 x 10(8) pfu), the uptake of (99m)Tc-labeled P2045 was 11.1% +/- 2.9 of injected dose per gram of tumor (thereafter, dose per gram), significantly higher (P.05) than the uptake of (131)I-labeled FIAU at 1.6% +/- 0.4 dose per gram. (99m)Tc-labeled P2045 imaging consistently depicted hSSTr2 gene transfer in tumors at all adenovirus doses. Tumor uptake of (99m)Tc-labeled P2045 positively correlated with Ad-hSSTr2-TK dose; (131)I-labeled FIAU tumor uptake did not correlate with vector dose.The hSSTr2 and TK proteins were simultaneously imaged following dual gene transfer with an adenovirus vector.

BACKGROUND Novel approaches to increasing the therapeutic efficacy of targeted radiotherapy of cancer are required. One strategy to achieve this goal is to induce high-level expression of a receptor on the surface of tumor cells that can be targeted with a radiolabeled peptide. The objectives of this study were to 1) induce somatostatin receptor (SSTr2) expression in tumor cells using an adenovirus encoding the SSTr2 gene (AdSSTr2), 2) demonstrate tumor localization of [111In]-DTPA-D-Phe1-octreotide in AdSSTr2-injected tumors, and 3) show therapeutic efficacy with [90Y]-DOTA-D-Phe1-Tyr3-octreotide ([90Y]-SMT 487). METHODS SSTr2 expression was validated in vitro by the binding and subsequent internalization of [111In]-DTPA-D-Phe1-octreotide (21.3% per mg of total protein) in A-427 cells infected with AdSSTr2. In vivo imaging confirmed 5- to 10-fold greater uptake 5.5 hours after intravenous administration of [111In]-DTPA-D-Phe1-octreotide in AdSSTr2-injected tumors relative to control tumors. For therapy studies, mice bearing established subcutaneous A-427 tumors were given two intratumoral injections of AdSSTr2 1 week apart, followed by an intravenous injection of 400 μCi or 500 μCi [90Y]-SMT 487 at 2 and 4 days after each adenoviral administration. Control animals either were not treated or were administered 500 μCi [90Y]-SMT 487 with no AdSSTr2 injection. RESULTS These studies showed that untreated animals and animals treated with no virus and 500 μCi [90Y]-SMT 487 had median tumor quadrupling times of 16 and 25 days, respectively. Mice administered AdSSTr2 and either 400 μCi or 500 μCi of [90Y]-SMT 487 demonstrated significantly longer median tumor quadrupling times of 40 and 44 days, respectively (P < 0.02). CONCLUSIONS These studies are the first to demonstrate in vivo therapeutic efficacy using a radiolabeled peptide targeted to a receptor expressed on the surface of tumor cells following gene transfer. Future studies will focus on the optimization of this approach. Cancer 2002;94:1298–1305. © 2002 American Cancer Society. DOI 10.1002/cncr.10300

The acquired immunodeficiency syndrome (AIDS) was first recognized in 1981 (Blattner, 1991) and has become the most globally devastating of the emerging infectious diseases threatening human health in the 21st century. AIDS can be caused by either of the two human immunodeficiency viruses, HlV-1 and HIV-2. It is estimated that so far around 60 million people have been infected by these viruses, of whom 19 million have died of AIDS (UNAIDS, 2001). Combination antiviral therapies have provided clinical relief to some, but these treatments can have toxic sideeffects, and due to their expense these drugs have not yet been widely available in many of the countries worst affected by AIDS. Given the sudden appearance of AIDS in the 20th century, there is an obvious interest in understanding the origins and evolution of the causative viruses, not least in the context of attempts to prevent further such diseases (Hahn et al., 2000).

Objective. Gene therapy trials for ovarian cancer would benefit from a noninvasive imaging modality to detect the location and extent of gene transfer. The human type 2 somatostatin receptor gene (hSSTr2) was evaluated as a reporter gene for imaging adenoviral (Ad) gene transfer to ovarian cancer. Methods. A replication-incompetent Ad vector encoding hSSTr2 (Ad-hSSTr2) was used to infect SKOV3.ip1 cells in vitro and tumors growing in nude mice. Gamma camera imaging detected uptake of 99m-Tc-P2045 (a somatostatin analogue) due to expressed hSSTr2. Results. Specific uptake of 99m-Tc-P2045 was imaged in Ad-hSSTr2-infected cells in vitro. Noninvasive in vivo imaging detected gene transfer to intraperitoneal tumors. Uptake of 99m-Tc-P2045 (percentage dose per gram of tumor) averaged 2.2 and 0.18 for Ad-hSSTr2-injected mice and controls, respectively. Conclusion. This study reports the first noninvasive imaging method for imaging gene transfer to ovarian cancer. A human gene therapy trial is planned.