The use of dose quantities in radiological protection: ICRP publication 147 Ann ICRP 50(1) 2021.

The International Commission on Radiological Protection has recently published a report (ICRP Publication 147;Ann. ICRP50, 2021) on the use of dose quantities in radiological protection, under the same authorship as this Memorandum. Here, we present a brief summary of the main elements of the report. ICRP Publication 147 consolidates and clarifies the explanations provided in the 2007 ICRP Recommendations (Publication 103) but reaches conclusions that go beyond those presented in Publication 103. Further guidance is provided on the scientific basis for the control of radiation risks using dose quantities in occupational, public and medical applications. It is emphasised that best estimates of risk to individuals will use organ/tissue absorbed doses, appropriate relative biological effectiveness factors and dose-risk models for specific health effects. However, bearing in mind uncertainties including those associated with risk projection to low doses or low dose rates, it is concluded that in the context of radiological protection, effective dose may be considered as an approximate indicator of possible risk of stochastic health effects following low-level exposure to ionising radiation. In this respect, it should also be recognised that lifetime cancer risks vary with age at exposure, sex and population group. The ICRP report also concludes that equivalent dose is not needed as a protection quantity. Dose limits for the avoidance of tissue reactions for the skin, hands and feet, and lens of the eye will be more appropriately set in terms of absorbed dose rather than equivalent dose.

Evaluation of universal immunohistochemical screening of sebaceous neoplasms in a service setting.

BACKGROUND: Muir-Torre syndrome (MTS) is a subtype of Lynch syndrome, which encompasses the combination of sebaceous skin tumours or keratoacanthomas and internal malignancy, due to mutations in DNA mismatch repair genes. Sebaceous neoplasms (SNs) may occur before other malignancies, and may lead to the diagnosis, which allows testing of other family members, cancer surveillance, risk-reducing surgery or prevention therapies. AIM: To evaluate the efficacy of universal immunohistochemistry (IHC) screening of SNs in a service setting. METHODS: Patients with SNs were ascertained by a regional clinical pathology service over a 3-year period. Results of tumour IHC, clinical genetics notes and germline genetic testing were retrospectively reviewed. RESULTS: In total, 62 patients presented with 71 SNs; 9 (15%) of these patients had previously diagnosed MTS. Tumour IHC was performed for 50 of the 53 remaining patients (94%); 26 (52%) had loss of staining of one or more mismatch repair proteins. Fifteen patients were referred to the Clinical Genetics department, and 10 patients underwent germline genetic testing. Two had a new diagnosis of MTS confirmed, with heterozygous pathogenic mutations detected in the MSH2 and PMS2 genes (diagnostic yield 20%). The PMS2 mutation was identified in a 57-year-old woman with a sebaceous adenoma and history of endometrial cancer; to our knowledge, this is the first time a PMS2 mutation has been reported in MTS. CONCLUSIONS: Universal IHC screening of SNs is an effective method to identify cases for further genetic evaluation. Rates of referral to clinical genetics were only moderate (58%). Increased awareness of MTS could help improve the rate of onward referral.

Inflammatory Cytokines, Endothelial Function, and Chronic Allograft Vasculopathy in Children: An Investigation of the Donor and Recipient Vasculature After Heart Transplantation.

Chronic allograft vasculopathy (CAV) limits the lifespan of pediatric heart transplant recipients. We investigated blood markers of inflammation, endothelial dysfunction, and damage to both the native and transplanted vasculature in children after heart transplantation. Serum samples were taken from pediatric heart transplant recipients for markers of inflammation and endothelial activation. The systemic vasculature was investigated using brachial artery flow-mediated dilatation and carotid artery intima-medial hyperplasia. CAV was investigated using intravascular ultrasound. Mean intima-media thickness (mIMT) > 0.5 mm was used to define significant CAV. Forty-eight children (25 male) aged 8-18 years were enrolled in the study. Patients were a median (interquartile range) 4.1 (2.2-8.7) years after transplant. Patients had increased levels of circulating IL6 (3.86 [2.84-4.95] vs. 1.66 [1.22-2.63] p < 0.0001), vascular cell adhesion molecule 1 (539 [451-621] vs. 402 [342-487] p < 0.001), intracellular adhesion molecule 1 305 (247-346) vs. 256 (224-294) p = 0.002 and thrombomodulin (7.1 [5.5-8.1] vs. 3.57 [3.03-4.71] p < 0.0001) and decreased levels of tumor necrosis factor-α, E selectin, and P selectin, compared with controls. The systemic vasculature was unaffected. Patients with severe CAV had raised serum von Willebrand factor and decreased serum thrombomodulin. Posttransplant thrombomodulin levels are elevated after transplant but significantly lower in those with mIMT > 0.5 mm. This suggests that subclinical inflammation is present and that natural anticoagulant/thrombomodulin activity is important after transplant.

Successful orthotopic heart transplantation using a donor heart with ALCAPA.

With the imbalance between donation rates and potential recipients growing, transplant programs are increasingly using non-ideal organs from so-called marginal donors. This is the first reported case of the intentional use of a donor heart with ALCAPA. The recipient was aged one yr with restrictive cardiomyopathy who had been supported with BiVAD for over six months. Function of the donor left ventricle was shown to be well preserved, with no obvious signs of ischemia, except for a fibrotic layer on the anterolateral papillary muscle of the mitral valve. To prevent coronary steal, the anomalous left coronary artery ostium from the MPA was oversewn prior to implantation. The transplanted heart spontaneously regained sinus rhythm immediately following cross-clamp release and showed good contractility from the first postoperative echocardiogram. The patient continues to do well 18 months post-transplant, with excellent function on echocardiography, and good flow on coronary angiography.

A case-control study assessing bone mineral density in severe haemophilia A in the UK.

It has been shown that bone mineral density (BMD) may be lower in patients with haemophilia (PWH). A comparison to control subjects is required to thoroughly assess current BMD in PWH in the UK. The objective of this study was to test the hypothesis that BMD is lower in PWH than in controls, and in patients with more severely affected joints or lower activity levels. In this case-control study, 37 patients with severe haemophilia A were recruited from two haemophilia centres in the UK. A group of 37 age, gender and ethnicity-matched control participants were recruited. All participants had a bone density scan, a musculoskeletal assessment, a blood test for vitamin D and completed a functional activity questionnaire. Of the case group, 5% had osteoporosis and 24% had BMD lower than expected for age. No control participants had osteoporosis, 3% had osteopenia and 14% had BMD lower than expected for age. Ninety one per cent of case participants and 92% of control participants had reduced 25(OH)D levels. Case participants had significantly lower BMD than control participants, and case participants with more severely affected joints, lower activity levels, HIV, history of hepatitis C or lower BMI had significantly lower BMD. Patients with severe haemophilia have a higher risk of low BMD than men without haemophilia. Patients with more severely affected joints and lower activity levels have lower BMD. It remains unclear whether patients with low BMD reached adequate peak bone mass. Low vitamin D may be present in the majority of PWH.

Xenon tracers for cost effective laser induced fluorescence of alternative propellant Hall thrusters.

One of the limiting factors to developing plasma thrusters on alternative propellants is the cost associated with changing the diagnostic tools, which are often propellant-dependent. For laser induced fluorescence (LIF), which is typically used for ion velocity distribution measurements to determine ion trajectories and potential profiles, either new lasers need to be bought, which are tuned to the wavelength of the new element's excitation level, or a costly tunable laser is required. A method to use existing LIF setups designed for xenon on any propellant has been demonstrated on a Hall thruster operating on krypton. In the demonstration test, a small amount of xenon (0.01%-4%) was mixed with the main krypton propellant for use as a diagnostic tracer, and xenon ion velocities were measured while also monitoring changes in the mean discharge current and oscillations. High signal-to-noise ratios in LIF data acquired along the channel centerline were obtained with tracer gas fractions ≤1% that negligibly affected the thruster operation. These results and comparison of the emission spectra of xenon and other common propellants suggest that the tracer LIF method should be broadly applicable to LIF measurements in Hall thrusters operating on alternative propellants.

Masterclass: Hypermobility and hypermobility related disorders.

INTRODUCTION: Hypermobile joints display a range of movement that is considered excessive, taking into consideration the age, gender and ethnic background of the individual. Joint hypermobility may present in a single joint, a few joints or in multiple joints and may be congenital or acquired with training, disease or injury. Hypermobile joints may be asymptomatic or may be associated with pain, fatigue, multisystemic complaints and significant disability. Furthermore, joint hypermobility may be a sign of an underlying hereditary disorder of connective tissue. PURPOSE: This masterclass aims to provides a state-of-the-art review of the aetiology, epidemiology, clinical presentation, assessment and management of joint hypermobility and hypermobility related disorders using an evidence based and biopsychosocial approach. The new framework for classifying the spectrum of joint hypermobility disorders along with new diagnostic criteria for the hypermobile Ehlers Danlos syndrome, published by an international consortium of clinical experts and researchers in 2017 is integrated into the paper. IMPLICATIONS FOR PRACTICE: People with joint hypermobility related disorders present to healthcare professionals with a wide range of symptoms which extend beyond the musculoskeletal system. Early recognition and treatment are key to effective management. A biopsychosocial and patient empowerment approach to functional restoration is recommended.

Health promotion: How government can ensure that the National Health Insurance Fund has a fighting chance.

Health promotion - keeping people healthy - is critical to ensuring that South Africa (SA)'s National Health Insurance (NHI) services and funding will not be overwhelmed by having to service and pay for large numbers of people with avoidable disease. Although the 2019 NHI Bill mentions health promotion, its lack of emphasis and the narrow approach proposed in the Bill make it unlikely that health promotion will have significant impact on population health or reducing healthcare need. Health promotion experts submit that there is in fact huge potential for carefully planned and researched health promotion to impact on population health. The establishment of a multisectoral National Health Commission or an independent Health Promotion and Development Foundation linked directly to the NHI Fund that includes several relevant government departments and civil society and researchers is proposed. Of the NHI Fund, 2% should be dedicated specifically to promoting health and preventing illness, which must support comprehensive, multisectoral health promotion interventions that go beyond awareness raising and health education. SA's specific realities and needs, including poverty and its related behavioural impacts and health consequences, must be taken into account.

Comparative Study of Pediatric Coronary Allograft Vasculopathy Between Single Centers in North America and United Kingdom.

BACKGROUND: Coronary allograft vasculopathy (CAV) is the leading cause of death after pediatric heart transplantation from 1 year postoperation. Anecdotal evidence suggests a difference in the severity of disease between UK and North America. We performed a comparative study using intravascular ultrasound (IVUS). METHODS: Consecutive IVUS procedures from a single year were included from each center. Using standardized techniques, measurement of the vessel area, lumen area, and maximal intimamedial thickening (IMT) were performed with calculation of intimal index (II) for each slice. Mean II, mean IMT, and absolute maximum IMT were calculated along the left coronary artery for each patient. Transplant demographics and treatment details were included in the analysis. RESULTS: One hundred four patients were included between the 2 centers. Interobserver variability for IVUS analysis was excellent. Patients were aged mean 14.2 (SD 3.3) years at the time of the study and 9.2 (SD 6.0) years earlier post-transplant procedure. UK patients were older, at transplant for a shorter time, and demonstrated more severe CAV. Multiple regression analysis demonstrated the detrimental effect of donor age and time from transplant on CAV severity and benefits of sirolimus use. CONCLUSIONS: The data show more severe CAV in the UK cohort despite significantly shorter time post-transplant. Donor age and time post-transplant were associated with more severe CAV and sirolimus use was associated with a reduction in IMT. This study demonstrates a marked difference in the prevalence of CAV in children between UK and North America. The causes are likely to be multifactorial; however, younger donors and recipients have significantly less disease.

Physiotherapy management of joint hypermobility syndrome--a focus group study of patient and health professional perspectives.

OBJECTIVE: To develop an understanding of patient and health professional views and experiences of physiotherapy to manage joint hypermobility syndrome (JHS). DESIGN: An explorative qualitative design. Seven focus groups were convened, audio recorded, fully transcribed and analysed using a constant comparative method to inductively derive a thematic account of the data. SETTING: Four geographical areas of the U.K. PARTICIPANTS: 25 people with JHS and 16 health professionals (14 physiotherapists and two podiatrists). RESULTS: Both patients and health professionals recognised the chronic heterogeneous nature of JHS and reported a lack of awareness of the condition amongst health professionals, patients and wider society. Diagnosis and subsequent referral to physiotherapy services for JHS was often difficult and convoluted. Referral was often for acute single joint injury, failing to recognise the long-term multi-joint nature of the condition. Health professionals and patients felt that if left undiagnosed, JHS was more difficult to treat because of its chronic nature. When JHS was treated by health professionals with knowledge of the condition patients reported satisfactory outcomes. There was considerable agreement between health professionals and patients regarding an 'ideal' physiotherapy service. Education was reported as an overarching requirement for patients and health care professionals. CONCLUSIONS: Physiotherapy should be applied holistically to manage JHS as a long-term condition and should address injury prevention and symptom amelioration rather than cure. Education for health professionals and patients is needed to optimise physiotherapy provision. Further research is required to explore the specific therapeutic actions of physiotherapy for managing JHS.

Use of effective dose.

International Commission on Radiological Protection (ICRP) Publication 103 provided a detailed explanation of the purpose and use of effective dose and equivalent dose to individual organs and tissues. Effective dose has proven to be a valuable and robust quantity for use in the implementation of protection principles. However, questions have arisen regarding practical applications, and a Task Group has been set up to consider issues of concern. This paper focusses on two key proposals developed by the Task Group that are under consideration by ICRP: (1) confusion will be avoided if equivalent dose is no longer used as a protection quantity, but regarded as an intermediate step in the calculation of effective dose. It would be more appropriate for limits for the avoidance of deterministic effects to the hands and feet, lens of the eye, and skin, to be set in terms of the quantity, absorbed dose (Gy) rather than equivalent dose (Sv). (2) Effective dose is in widespread use in medical practice as a measure of risk, thereby going beyond its intended purpose. While doses incurred at low levels of exposure may be measured or assessed with reasonable reliability, health effects have not been demonstrated reliably at such levels but are inferred. However, bearing in mind the uncertainties associated with risk projection to low doses or low dose rates, it may be considered reasonable to use effective dose as a rough indicator of possible risk, with the additional consideration of variation in risk with age, sex and population group.

Neonatal nitric oxide synthase inhibition: social interaction deficits in adulthood and reversal by antipsychotic drugs.

Nitric oxide synthase (NOS) is thought to migrate improperly during development in the brains of schizophrenic patients. Also it is known that nitric oxide (NO) effects synaptogenesis during development of the CNS. Previously we have shown that neonatal treatment with a NOS inhibitor effects an animal's sensitivity to amphetamine and PCP. In the present study, neonatal rats were challenged with a NOS inhibitor (L-nitroarginine, 10mg/kg, s.c.) daily on post-natal days (PD) three, four and five. L-Nitroarginine (L-NoArg) treated male rats at adulthood (PD56 and older) had a deficit in social interaction (SI) when placed in an environment with another foreign male rat and this deficit was reproducible on a weekly basis for at least five weeks. Haloperidol failed to significantly reverse this deficit before pronounced secondary effects on general behavior were seen at high doses. However, the atypical antipsychotics, clozapine and olanzapine, were able to significantly reverse this deficit at doses which did not effect baseline SI values. In a separate cohort of animals the effect of DOI was investigated, this was done to ascertain if there was a differential sensitivity of serotonergic pathways in this model. There was no difference in the behavioral score elicited from control or NoArg-treated rats. It is suggested that the SI deficits seen here may be more sensitive to atypical antipsychotics rather than haloperidol.

Potent quinoxaline-spaced phosphono alpha-amino acids of the AP-6 type as competitive NMDA antagonists: synthesis and biological evaluation.

A series of alpha-amino-3-(phosphonoalkyl)-2-quinoxalinepropanoic acids was synthesized and evaluated for NMDA receptor affinity using a [3H] CPP binding assay. Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated [3H]TCP binding assay and in vivo by employing an NMDA-induced seizure model. Some analogues also were evaluated in the [3H]-glycine binding assay. Several compounds of the AP-6 type show potent and selective NMDA antagonistic activity both in vitro and in vivo. In particular alpha-amino-7-chloro-3-(phosphonomethyl)-2-quinoxalinepropanoic acid (1) displayed an ED50 of 1.1 mg/kg ip in the NMDA lethality model. Noteworthy is alpha-amino-6,7-dichloro-3-(phosphonomethyl)-2-quinoxalinepropanoic++ + acid (3) with a unique dual activity, displaying in the NMDA receptor binding assay an IC50 of 3.4 nM and in the glycine binding assay an IC50 of 0.61 microM.

Bioisosteric replacement of the alpha-amino carboxylic acid functionality in 2-amino-5-phosphonopentanoic acid yields unique 3,4-diamino-3-cyclobutene-1,2-dione containing NMDA antagonists.

In this report, a novel bioisostere of the alpha-amino acid, 3,4-diamino-3-cyclobutene-1,2-dione, has been incorporated into a series of compounds which are NMDA antagonists. These compounds, which are achiral and easily prepared, demonstrated good affinity at the NMDA receptor by their ability to displace [3H]CPP binding in vitro. In particular, the phosphonic acid 24 provided protection against NMDA-induced lethality in mice equivalent to 2-amino-7-phosphonoheptanoic acid (5). This was considered an encouraging result in lieu of the fact that 24, like 5, lacks the conformational rigidity of the more potent NMDA antagonists. In addition, analogs that incorporate the 1,2,4-oxadiazolidine-3,5-dione heterocycle of quisqualic acid and the unsaturation of kainic acid were prepared to explore selectivity at the non-NMDA receptor subtypes.

Fusarium solani osteomyelitis with probable nosocomial spread.

A case of Fusarium solani osteomyelitis is reported in a previously healthy adult male who received multiple injuries during an automobile accident. Combined histologic and mycologic data proved it to be a case of hyalohyphomycosis resulting from Fusarium. To the best of the authors' knowledge, this is the first reported case of osteomyelitis resulting from F. solani. A concurrent case of saprophytic wound colonization by the same organism is reported in another patient in the same ward who had sustained similar injuries. Evidence suggests that this represents nosocomial spread from the first case.

A constitutive gene expression system derived from the tCUP cryptic promoter elements.

A limited number of constitutive promoters have been used to direct transgene expression in plants and they are often derived from non-plant sources. Here, we describe novel gene-regulatory elements which are associated with a cryptic constitutive promoter from tobacco, tCUP, and modifications that were made to create a strong gene-expression system that is effective across all living cell types from a wide range of plant species, including several important crops ( Arabidopsis, canola, flax, alfalfa, tobacco). The tCUP 5' untranslated region was mutated to eliminate translational interference by upstream ATGs, and the influence of the Kozak consensus sequence on the levels of a beta-glucuronidase (GUS) reporter gene activity was demonstrated. These modifications resulted in expression that was greatly enhanced in all organs. A TATA consensus sequence was added to the core promoter to complement an existing Initiator (Inr) sequence. Although this addition was known to elevate core promoter activity by 3-fold the additive effect on the overall gene-expression system was marginal in all of the transgenic plants tested. Two transcriptional enhancers were identified and the region containing them were oligomerized, yielding a significant increase in marker gene-expression in some but not all plant species. In general, the enhanced tCUP gene-expression system generated levels of GUS activity which exceeded that of the 35S promoter in most plant species and the elevation in activity occurred uniformly among the various plant organs. The potential benefit of cryptic elements for the construction of gene-expression systems for crop species is discussed

Effect of dexamethasone on monoamine and metabolite levels in a brain-tumor model.

Neurological improvement in brain-tumor patients treated with dexamethasone (DEX) precedes a reduction in peritumor brain edema. In the study reported here, levels of noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT), homovanillic acid (HVA) and 5-hydroxyindole-3-acetic acid (5-HIAA) and tissue water content were measured in grey and white matter adjacent to a 9L glioma in the cat to study DEX-neurotransmitter interactions as possible mechanisms for the acute neurological effects of DEX. Tumor-bearing and control cats were treated or not treated with DEX (0.25 mg/kg IV, 0.25 mg/kg IM) with 0.25 mg/kg IM repeated once (DEX 1) or 3 times (DEX 2) 6 hr apart. In control animals DEX 1 treatment led to significant decreases in concentration of DOPAC; DEX 2 treatment led to increases in HVA and 5-HIAA. Peritumor grey matter from untreated tumor-bearing animals had decreased levels of NA and DA and the metabolite DOPAC with no changes in 5-HT and 5-HIAA. DEX 2 but not DEX 1 resulted in a normalization (increase) in peritumor levels of DA and DOPAC. Neither dose of DEX reduced white matter edema. These findings suggest that the acute beneficial effect of DEX on neurological status may be due to alleviation of neurotransmitter amine and metabolite depletion.

Inhibition of ischemia-induced brain catecholamine alterations by clonidine.

The effect of clonidine, an alpha 2-agonist, on ischemia-induced alterations in brain catecholamine and metabolite levels was studied in Mongolian gerbils subjected to 180 min of unilateral cerebral ischemia. The gerbils were randomly assigned to four treatment groups: sham-operated or unilateral carotid lesion; each pretreated with clonidine 0.4 mg/kg IP, or untreated. All animals were neurologically assessed and categorized as asymptomatic, neurological deficit or seizure activity at the time of sacrifice. Hemispheric levels of noradrenaline (NA), dopamine (DA), homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured using high pressure liquid chromatography with electrochemical detection. No changes from control were found in animals that remained asymptomatic regardless of treatment. In untreated gerbils that exhibited neurological deficits, marked reductions in both NA and DA and increases in HVA occurred in the ischemic hemisphere. These alterations were greater in gerbils that developed seizures during the observation period. Ischemic animals pretreated with clonidine did not show any significant alterations in catecholamine or metabolite levels from clonidine-treated, sham-operated controls in spite of the presence of neurological deficits. Although significant reductions in NA and DA still occurred in pretreated animals that developed seizures, the changes were markedly less than in untreated gerbils. These results indicate that alpha 2-adrenoceptor stimulation is an effective approach for inhibition of ischemia-induced brain catecholamine alterations, and thus may provide a useful method for assessing the role of catecholamine release in the production of acute ischemic neuronal damage.