Models of Disability as Research Frameworks in Biology Education Research.

Advancing equity and justice in undergraduate biology education requires research to address the experiences of disabled students. Scholars working in disability studies have developed models of disability that inform Discipline-Based Education Research (DBER). To date, DBER literature has been predominantly informed by the medical and social models of disability. The medical model focuses on challenges that affect people with disabilities on an individual basis, while the social model focuses on how one's surrounding environment contributes to the construction of disability. In this essay, we discuss past DBER research and opportunities for future research using each of these models. We will also discuss a third, less commonly used model that offers exciting opportunities to drive future research: complex embodiment. Complex embodiment positions disability as a social location that reflects a greater societal value structure. Further examining this value structure reveals how ability itself is constructed and conventionally understood to be hierarchical. Additionally, we explain epistemic injustice as it affects disabled people, and how future education research can both address and counteract this injustice. We discuss how expanding the frameworks that serve as lenses for DBER scholarship on disability will offer new research directions.

Psilocybin induces acute and persisting alterations in immune status in healthy volunteers: An experimental, placebo-controlled study.

Patients characterized by stress-related disorders such as depression display elevated circulating concentrations of pro-inflammatory cytokines and a hyperactive HPA axis. Psychedelics are demonstrating promising results in treatment of such disorders, however the mechanisms of their therapeutic effects are still unknown. To date the evidence of acute and persisting effects of psychedelics on immune functioning, HPA axis activity in response to stress, and associated psychological outcomes is preliminary. To address this, we conducted a placebo-controlled, parallel group design comprising of 60 healthy participants who received either placebo (n = 30) or 0.17 mg/kg psilocybin (n = 30). Blood samples were taken to assess acute and persisting (7 day) changes in immune status. Seven days' post-administration, participants in each treatment group were further subdivided: 15 underwent a stress induction protocol, and 15 underwent a control protocol. Ultra-high field (7-Tesla) magnetic resonance spectroscopy was used to assess whether acute changes in glutamate or glial activity were associated with changes in immune functioning. Finally, questionnaires assessed persisting self-report changes in mood and social behavior. Psilocybin immediately reduced concentrations of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α), while other inflammatory markers (interleukin (IL)- 1ß, IL-6, and C-reactive protein (CRP)) remained unchanged. Seven days later, TNF-α concentrations returned to baseline, while IL-6 and CRP concentrations were persistently reduced in the psilocybin group. Changes in the immune profile were related to acute neurometabolic activity as acute reductions in TNF-α were linked to lower concentrations of glutamate in the hippocampus. Additionally, the more of a reduction in IL-6 and CRP seven days after psilocybin, the more persisting positive mood and social effects participants reported. Regarding the stress response, after a psychosocial stressor, psilocybin did not significantly alter the stress response. Results are discussed in regards to the psychological and therapeutic effects of psilocybin demonstrated in ongoing patient trials.

Functional brain connectomes reflect acute and chronic cannabis use.

Resting state fMRI has been employed to identify alterations in functional connectivity within or between brain regions following acute and chronic exposure to Δ9-tetrahydrocannabinol (THC), the psychoactive component in cannabis. Most studies focused a priori on a limited number of local brain areas or circuits, without considering the impact of cannabis on whole-brain network organization. The present study attempted to identify changes in the whole-brain human functional connectome as assessed with ultra-high field (7T) resting state scans of cannabis users (N = 26) during placebo and following vaporization of cannabis. Two distinct data-driven methodologies, i.e. network-based statistics (NBS) and connICA, were used to identify changes in functional connectomes associated with acute cannabis intoxication and history of cannabis use. Both methodologies revealed a broad state of hyperconnectivity within the entire range of major brain networks in chronic cannabis users compared to occasional cannabis users, which might be reflective of an adaptive network reorganization following prolonged cannabis exposure. The connICA methodology also extracted a distinct spatial connectivity pattern of hypoconnectivity involving the dorsal attention, limbic, subcortical and cerebellum networks and of hyperconnectivity between the default mode and ventral attention network, that was associated with the feeling of subjective high during THC intoxication. Whole-brain network approaches identified spatial patterns in functional brain connectomes that distinguished acute from chronic cannabis use, and offer an important utility for probing the interplay between short and long-term alterations in functional brain dynamics when progressing from occasional to chronic use of cannabis.

Breast cancer-secreted factors perturb murine bone growth in regions prone to metastasis.

Breast cancer frequently metastasizes to bone, causing osteolytic lesions. However, how factors secreted by primary tumors affect the bone microenvironment before the osteolytic phase of metastatic tumor growth remains unclear. Understanding these changes is critical as they may regulate metastatic dissemination and progression. To mimic premetastatic bone adaptation, immunocompromised mice were injected with MDA-MB-231-conditioned medium [tumor-conditioned media (TCM)]. Subsequently, the bones of these mice were subjected to multiscale, correlative analysis including RNA sequencing, histology, micro-computed tomography, x-ray scattering analysis, and Raman imaging. In contrast to overt metastasis causing osteolysis, TCM treatment induced new bone formation that was characterized by increased mineral apposition rate relative to control bones, altered bone quality with less matrix and more carbonate substitution, and the deposition of disoriented mineral near the growth plate. Our study suggests that breast cancer-secreted factors may promote perturbed bone growth before metastasis, which could affect initial seeding of tumor cells.

Development of a PET radioligand selective for cerebral amyloid angiopathy.

INTRODUCTION: Positron emission tomography (PET) using radiolabeled amyloid-binding compounds has advanced the field of Alzheimer's disease (AD) by enabling detection and longitudinal tracking of fibrillar amyloid-ß (Aß) deposits in living people. However, this technique cannot distinguish between Aß deposits in brain parenchyma (amyloid plaques) from those in blood vessels (cerebral amyloid angiopathy, CAA). Development of a PET radioligand capable of selectively detecting CAA would help clarify its contribution to global brain amyloidosis and clinical symptoms in AD and would help to characterize side-effects of anti-Aß immunotherapies in AD patients, such as CAA. METHODS: A candidate CAA-selective compound (1) from a panel of analogues of the amyloid-binding dye Congo red was synthesized. The binding affinity to Aß fibrils and lipophilicity of compound 1 were determined and selectivity for CAA versus parenchymal plaque deposits was assessed ex-vivo and in-vivo in transgenic APP/PS1 mice and in postmortem human brain affected with AD pathology. RESULTS: Compound 1 displays characteristics of Aß binding dyes, such as thioflavin-S, in that it labels both parenchymal Aß plaques and CAA when applied to histological sections from both a transgenic APP/PS1 mouse model of Aß amyloidosis and AD brain. Thus, compound 1 lacks molecular selectivity to distinguish Aß deposits in CAA from those in plaques. However, when administered to living APP/PS1 mice intravenously, compound 1 preferentially labels CAA when assessed using in-vivo two-photon microscopy and ex-vivo histology and autoradiography. CONCLUSION: We hypothesize that selectivity of compound 1 for CAA is attributable to its limited penetration of the blood-brain barrier due to the highly polar nature of the carboxylate moiety, thereby limiting access to parenchymal plaques and promoting selective in-vivo labeling of Aß deposits in the vascular wall (i.e., "delivery selectivity").

Infrared attenuation due to phase change from amorphous to crystalline observed in astrochemical propargyl ether ices.

Astrochemical ices are known to undergo morphological changes, from amorphous to crystalline, upon warming the ice from lower (10 K) to higher temperatures. Phase changes are mostly identified by the observation of significant changes in the InfraRed (IR) spectrum, where the IR bands that are broad in the amorphous phase are narrower and split when the ice turns crystalline. To-date all the molecules that are studied under astrochemical conditions are observed to follow such a behaviour without significant attenuation in the IR wavelength. However, in this paper we report a new observation when propargyl ether (C3H3OC3H3) is warmed from the amorphous phase, at 10 K, through the phase transition temperature of 170 K, the crystalline ice being found to strongly attenuate IR photons at the mid-IR wavelengths.

Residue from vacuum ultraviolet irradiation of benzene ices: Insights into the physical structure of astrophysical dust.

We have irradiated benzene ices deposited at 4 K on a cold, interstellar dust analog with vacuum ultraviolet (9 eV) irradiation for periods lasting from several hours to nearly a day, after which the irradiated ice was warmed to room temperature. Vacuum ultraviolet photoabsorption spectra of the aromatic residue left at room temperature were recorded and showed the synthesis of benzene derivatives. The residue was also imaged using an electron microscope and revealed crystals of various sizes and shapes. The result of our experiments suggests such geometrically shaped dust particles may be a key component of interstellar dust.

Nociceptin Receptors Upregulated in Cocaine Use Disorder: A Positron Emission Tomography Imaging Study Using [11C]NOP-1A.

OBJECTIVE: Nociceptin/orphanin FQ (N/OFQ) is an antistress neuropeptide transmitter in the brain that counteracts corticotropin-releasing factor (CRF)-mediated stress and anxiety symptoms during drug and alcohol withdrawal. It also inhibits the release of a wide array of neurotransmitters, including dopamine and glutamate, which allows for it to block the rewarding properties of cocaine. Chronic cocaine administration in rodents has been shown to decrease N/OFQ and increase nociceptive opioid peptide (NOP) receptors in the nucleus accumbens. No previous studies have reported on the in vivo status of NOP in chronic cocaine-abusing humans. METHODS: [11C]NOP-1A and positron emission tomography (PET) were used to measure in vivo NOP binding in 24 individuals with cocaine use disorder and 26 healthy control subjects matched for age, sex, and smoking status. Participants with cocaine use disorder with no comorbid psychiatric or medical disorders were scanned after 2 weeks of outpatient-monitored abstinence. [11C]NOP-1A distribution volume (VT) was measured with kinetic analysis using the arterial input function in brain regions that mediate reward and stress behaviors. Participants with cocaine use disorder were followed up for 12 weeks after PET scanning to document relapse and relate it to VT. RESULTS: A significant increase in [11C]NOP-1A VT was observed in the cocaine use disorder group compared with the healthy control group. This increase, which was generalized across all regions of interest (approximately 10%), was most prominent in the midbrain, ventral striatum, and cerebellum. However, increased VT in these regions did not predict relapse. CONCLUSIONS: Increased NOP in cocaine use disorder suggests an adaptive response to decreased N/OFQ, or increased CRF transmission, or both. Future studies should examine the interactions between CRF and NOP to elucidate their role in negative reinforcement and relapse. NOP agonist medications to enhance N/OFQ should be explored as a therapeutic to treat cocaine use disorder.

A single inhalation of vapor from dried toad secretion containing 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) in a naturalistic setting is related to sustained enhancement of satisfaction with life, mindfulness-related capacities, and a decrement of psychopathological symptoms.

BACKGROUND: 5-methoxy-N,N-dimethyltryptamine (hereinafter referred to as 5-MeO-DMT) is a psychedelic substance found in the secretion from the parotoid glands of the Bufo alvarius toad. Inhalation of vapor from toad secretion containing 5-MeO-DMT has become popular in naturalistic settings as a treatment of mental health problems or as a means for spiritual exploration. However, knowledge of the effects of 5-MeO-DMT in humans is limited. AIMS: The first objective of this study was to assess sub-acute and long-term effects of inhaling vapor from dried toad secretion containing 5-MeO-DMT on affect and cognition. The second objective was to assess whether any changes were associated with the psychedelic experience. METHODS: Assessments at baseline, within 24 h and 4 weeks following intake, were made in 42 individuals who inhaled vapor from dried toad secretion at several European locations. RESULTS: Relative to baseline, ratings of satisfaction with life and convergent thinking significantly increased right after intake and were maintained at follow-up 4 weeks later. Ratings of mindfulness also increased over time and reached statistical significance at 4 weeks. Ratings of depression, anxiety, and stress decreased after the session, and reached significance at 4 weeks. Participants that experienced high levels of ego dissolution or oceanic boundlessness during the session displayed higher ratings of satisfaction with life and lower ratings of depression and stress. CONCLUSION: A single inhalation of vapor from dried toad secretion containing 5-MeO-DMT produces sub-acute and long-term changes in affect and cognition in volunteers. These results warrant exploratory research into therapeutic applications of 5-MeO-DMT.

Identification of a unique VUV photoabsorption band of carbonic acid for its identification in radiation and thermally processed water-carbon dioxide ices.

Carbonic acid was synthesized within an ice containing water and carbon dioxide by irradiation of ~9 eV photons. Vacuum UltraViolet (VUV)/UltraViolet (UV) photoabsorption spectra of the irradiated ice revealed absorption features from carbon dioxide, ozone, water, carbon monoxide and oxygen in addition to a band peaking at ~200 nm which is identified to be characteristic of carbonic acid. After thermal processing of the irradiated ice leading to desorption of the lower volatile ices, a pure carbonic acid spectrum is identified starting from 170 K until sublimation above 230 K. Therefore the ~200 nm band in the VUV region corresponding to carbonic acid is proposed to be a unique identifier in mixed ices, rich in water and carbon dioxide typically encountered on planetary and satellite surfaces.

Pre-procedural fit-testing of TAVR valves using parametric modeling and 3D printing.

BACKGROUND: Successful transcatheter aortic valve replacement (TAVR) requires an understanding of how a prosthetic valve will interact with a patient's anatomy in advance of surgical deployment. To improve this understanding, we developed a benchtop workflow that allows for testing of physical interactions between prosthetic valves and patient-specific aortic root anatomy, including calcified leaflets, prior to actual prosthetic valve placement. METHODS: This was a retrospective study of 30 patients who underwent TAVR at a single high volume center. By design, the dataset contained 15 patients with a successful annular seal (defined by an absence of paravalvular leaks) and 15 patients with a sub-optimal seal (presence of paravalvular leaks) on post-procedure transthoracic echocardiogram (TTE). Patients received either a balloon-expandable (Edwards Sapien or Sapien XT, n = 15), or a self-expanding (Medtronic CoreValve or Core Evolut, n = 14, St. Jude Portico, n = 1) valve. Pre-procedural computed tomography (CT) angiograms, parametric geometry modeling, and multi-material 3D printing were utilized to create flexible aortic root physical models, including displaceable calcified valve leaflets. A 3D printed adjustable sizing device was then positioned in the aortic root models and sequentially opened to larger valve sizes, progressively flattening the calcified leaflets against the aortic wall. Optimal valve size and fit were determined by visual inspection and quantitative pressure mapping of interactions between the sizer and models. RESULTS: Benchtop-predicted "best fit" valve size showed a statistically significant correlation with gold standard CT measurements of the average annulus diameter (n = 30, p < 0.0001 Wilcoxon matched-pairs signed rank test). Adequateness of seal (presence or absence of paravalvular leak) was correctly predicted in 11/15 (73.3%) patients who received a balloon-expandable valve, and in 9/15 (60%) patients who received a self-expanding valve. Pressure testing provided a physical map of areas with an inadequate seal; these corresponded to areas of paravalvular leak documented by post-procedural transthoracic echocardiography. CONCLUSION: We present and demonstrate the potential of a workflow for determining optimal prosthetic valve size that accounts for aortic annular dimensions as well as the active displacement of calcified valve leaflets during prosthetic valve deployment. The workflow's open source framework offers a platform for providing predictive insights into the design and testing of future prosthetic valves.

Companion animals in comparative oncology: One Medicine in action.

Comparative oncology is poised to have a far-reaching impact on both animals and human beings with cancer. The field is gaining momentum and has repeatedly proven its utility in various aspects of oncology, including study of the genetics, development, progression, immunology and therapy of cancer. Companion animals provide many advantages over both traditional rodent models and human beings for studying cancer biology and accelerating the development of novel anti-cancer therapies. In this review, several examples of the ability of companion animals with spontaneous cancers to fill a unique niche in the field of oncology are discussed. In addition, potential caveats of the use of companion animals in research are reviewed, as well as ethical considerations and efforts to standardize veterinary clinical trials.

Nociceptin Receptors in Alcohol Use Disorders: A Positron Emission Tomography Study Using [11C]NOP-1A.

BACKGROUND: The neuropeptide transmitter nociceptin, which binds to the nociceptin/orphanin FQ peptide (NOP) receptor, is a core component of the brain's antistress system. Nociceptin exerts its antistress effect by counteracting the functions of corticotropin-releasing factor, the primary stress-mediating neuropeptide in the brain. Basic investigations support a role for medications that target nociceptin receptors in the treatment of alcohol use disorders. Thus, it is of high interest to measure the in vivo status of NOP receptors in individuals with alcohol use disorders. METHODS: Here, we used [11C]NOP-1A and positron emission tomography to measure the in vivo binding to NOP receptors in 15 alcohol-dependent humans as identified by DSM-IV and 15 healthy control subjects matched for age, sex, and smoking status. Alcohol-dependent individuals with no comorbid psychiatric, medical, or drug abuse disorders were scanned following 2 weeks of outpatient monitored abstinence (confirmed with three times per week urine alcohol metabolite testing). [11C]NOP-1A distribution volume in regions of interest (including the amygdala, hippocampus, and midbrain, striatal, and prefrontal cortical subdivisions) was measured with kinetic analysis using the arterial input function. RESULTS: Regional [11C]NOP-1A distribution volume in alcohol dependence was not significantly different compared with healthy control subjects. No relationship between [11C]NOP-1A distribution volume and other clinical measures (including duration and severity of alcohol abuse, craving, and anxiety or depressive symptoms) were significant after correction for the multiple hypotheses tested. CONCLUSIONS: The results of this study do not support alterations in the binding to NOP receptors in alcohol dependence. However, this finding does not necessarily rule out alterations in nociceptin transmission in alcohol dependence.

Preclinical Evaluation of 18F-ML-10 to Determine Timing of Apoptotic Response to Chemotherapy in Solid Tumors.

PURPOSE: We investigated 2-(5-fluoro-pentyl)-2-methyl-malonic acid (18F-ML-10) positron emission tomography (PET) imaging of apoptosis posttherapy to determine optimal timing for predicting chemotherapy response in a mouse head/neck xenograft cancer model. PROCEDURES: BALB/c nude mice (4-8 weeks old) were implanted with UM-SCC-22B tumors. The treatment group received 2 doses of doxorubicin (10 mg/kg, days 0, 2). Small animal 18F-ML-10 PET/computed tomography was performed before and on days 1, 3, and 7 postchemotherapy. Using regions of interest around tumors, 18F-ML-10 uptake change was measured as %ID/g and uptake relative to liver. Terminal Uridine Nick-End Labeling (TUNEL) immunohistochemistry assay was performed using tumor samples of baseline and on days 1, 3, and 7 posttreatment. RESULTS: Treated mice demonstrated increased 18F-ML-10 uptake compared to baseline and controls, and 10 of 13 mice showed tumor volume decreases. All control mice showed tumor volume increases. Tumor-to-liver (T/L) ratios from the control group mice did not show significant change from baseline ( P > .05); however, T/L ratios of the treatment group showed significant 18F-ML-10 uptake differences from baseline compared to days 3 and 7 posttreatment ( P < .05), but no significant difference at 1 day posttreatment. CONCLUSION: 2-(5-Fluoro-pentyl)-2-methyl-malonic acid PET imaging has the potential for early assessment of treatment-induced apoptosis. Timing and image analysis strategies may require optimization, depending on the type of tumor and cancer treatment.

Toluene Valence and Rydberg Excitations as Studied by ab initio Calculations and Vacuum Ultraviolet (VUV) Synchrotron Radiation.

The electronic spectroscopy of isolated toluene in the gas phase has been investigated using high-resolution photoabsorption spectroscopy in the 4.0-10.8 eV energy range, with absolute cross-section measurements derived. We present the first set of ab initio calculations (vertical energies and oscillator strengths), which we use in the assignment of valence and Rydberg transitions of the toluene molecule. The spectrum reveals several new features not previously reported in the literature, with particular relevance to 7.989 and 8.958 eV, which are here tentatively assigned to the π*(17a') ← σ(15a') and 1π*(10a″) ← 1π(14a') transitions, respectively. The measured absolute photoabsorption cross sections have been used to calculate the photolysis lifetime of toluene in the upper stratosphere (20-50 km).

Electronic State Spectroscopy of Halothane As Studied by ab Initio Calculations, Vacuum Ultraviolet Synchrotron Radiation, and Electron Scattering Methods.

We present the first set of ab initio calculations (vertical energies and oscillator strengths) of the valence and Rydberg transitions of the anaesthetic compound halothane (CF3CHBrCl). These results are complemented by high-resolution vacuum ultraviolet photoabsorption measurements over the wavelength range 115-310 nm (10.8-4.0 eV). The spectrum reveals several new features that were not previously reported in the literature. Spin-orbit effects have been considered in the calculations for the lowest-lying states, allowing us to explain the broad nature of the 6.1 and 7.5 eV absorption bands assigned to σ*(C-Br) ← nBr and σ*(C-Cl) ← n(Cl) transitions. Novel absolute photoabsorption cross sections from electron scattering data were derived in the 4.0-40.0 eV range. The measured absolute photoabsorption cross sections have been used to calculate the photolysis lifetime of halothane in the upper stratosphere (20-50 km).

Colocation and role of polyphosphates and alkaline phosphatase in apatite biomineralization of elasmobranch tesserae.

Elasmobranchs (e.g. sharks and rays), like all fishes, grow continuously throughout life. Unlike other vertebrates, their skeletons are primarily cartilaginous, comprising a hyaline cartilage-like core, stiffened by a thin outer array of mineralized, abutting and interconnected tiles called tesserae. Tesserae bear active mineralization fronts at all margins and the tesseral layer is thin enough to section without decalcifying, making this a tractable but largely unexamined system for investigating controlled apatite mineralization, while also offering a potential analog for endochondral ossification. The chemical mechanism for tesserae mineralization has not been described, but has been previously attributed to spherical precursors, and alkaline phosphatase (ALP) activity. Here, we use a variety of techniques to elucidate the involvement of phosphorus-containing precursors in the formation of tesserae at their mineralization fronts. Using Raman spectroscopy, fluorescence microscopy and histological methods, we demonstrate that ALP activity is located with inorganic phosphate polymers (polyP) at the tessera-uncalcified cartilage interface, suggesting a potential mechanism for regulated mineralization: inorganic phosphate (Pi) can be cleaved from polyP by ALP, thus making Pi locally available for apatite biomineralization. The application of exogenous ALP to tissue cross-sections resulted in the disappearance of polyP and the appearance of Pi in uncalcified cartilage adjacent to mineralization fronts. We propose that elasmobranch skeletal cells control apatite biomineralization by biochemically controlling polyP and ALP production, placement and activity. Previous identification of polyP and ALP shown previously in mammalian calcifying cartilage supports the hypothesis that this mechanism may be a general regulating feature in the mineralization of vertebrate skeletons.

Determination of degree of ionization of poly(allylamine hydrochloride) (PAH) and poly[1-[4-(3-carboxy-4 hydroxyphenylazo)benzene sulfonamido]-1,2-ethanediyl, sodium salt] (PAZO) in layer-by-layer films using vacuum photoabsorption spectroscopy.

Electrostatic and hydrophobic interactions govern most of the properties of supramolecular systems, which is the reason determining the degree of ionization of macromolecules has become crucial for many applications. In this paper, we show that high-resolution ultraviolet spectroscopy (VUV) can be used to determine the degree of ionization and its effect on the electronic excitation energies of layer-by-layer (LbL) films of poly(allylamine hydrochloride) (PAH) and poly[1-[4-(3-carboxy-4 hydroxyphenylazo)benzene sulfonamido]-1,2-ethanediyl, sodium salt] (PAZO). A full assignment of the VUV peaks of these polyelectrolytes in solution and in cast or LbL films could be made, with their pH dependence allowing us to determine the pK(a) using the Henderson-Hasselbach equation. The pK(a) for PAZO increased from ca. 6 in solution to ca. 7.3 in LbL films owing to the charge transfer from PAH. Significantly, even using solutions at a fixed pH for PAH, the amount adsorbed on the LbL films still varied with the pH of the PAZO solutions due to these molecular-level interactions. Therefore, the procedure based on a comparison of VUV spectra from solutions and films obtained under distinct conditions is useful to determine the degree of dissociation of macromolecules, in addition to permitting interrogation of interface effects in multilayer films.

A management algorithm for congenital erythropoietic porphyria derived from a study of 29 cases.

BACKGROUND: Congenital erythropoietic porphyria (CEP) is an autosomal recessive photomutilating porphyria with onset usually in childhood, where haematological complications determine prognosis. Due to its extreme rarity and clinical heterogeneity, management decisions in CEP are often difficult. OBJECTIVES: To develop a management algorithm for patients with CEP based on data from carefully characterized historical cases. METHODS: A single investigator collated data related to treatments and their outcomes in 29 patients with CEP from the U.K., France, Germany and Switzerland. RESULTS: Six children were treated with bone marrow transplantation (BMT); five have remained symptomatically cured up to 11.5 years post-transplantation. Treatments such as oral charcoal, splenectomy and chronic hypertransfusion were either of no benefit or were associated with complications and negative impact on health-related quality of life. Lack of consistent genotype-phenotype correlation meant that this could not be used to predict disease prognosis. The main poor prognostic factors were early age of disease onset and severity of haematological manifestations. CONCLUSIONS: A management algorithm is proposed where every patient, irrespective of disease severity at presentation, should receive a comprehensive, multidisciplinary clinical assessment and should then be reviewed at intervals based on their predicted prognosis, and the rate of onset of complications. A BMT should be considered in those with progressive, symptomatic haemolytic anaemia and/or thrombocytopenia. Uroporphyrinogen III synthase genotypes associated with poor prognosis would additionally justify consideration for a BMT. Rigorous photoprotection of the skin and eyes from visible light is essential in all patients.