Oral and oesophageal squamous cell carcinoma--a complication or component of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS-I)

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autosomal recessive disease exceptionally common in Finland. It is associated with a limited T lymphocyte defect, an autoimmune response to various tissues, particularly endocrine glands. Most patients have chronic oral candidosis, which has been suggested to be carcinogenic. In Finland 92 patients have been diagnosed with APECED and 66 of them are alive. Our aim was to study the possible association of APECED with oral and oesophageal carcinoma. We evaluated the medical histories of all 92 patients for morbidity, causes of death, and known risk factors for oral cancer. We invited all current patients for a clinical examination of their oral mucosa. Six of the 92 had developed oral or oesophageal squamous cell carcinoma (SCC) by the mean age of 37 (29-44years) and four of them had died from it. The six represent 10% of the patients older than 25years. Five of the six patients had long-lasting oral candidosis. Four of the six had smoked regularly for 15years or more. One patient had been on immunosuppressive therapy for 6years following kidney transplantation when SCC in her mouth occurred. The partial T cell defect of APECED seems to favour the growth of Candida albicans and predispose to chronic mucositis and SCC. Aggressive control of oral candidosis and close follow-up of oral mucosa is a necessity in patients with APECED.     

Recording lead V(4)R is associated to enhanced use of fibrinolytic therapy in acute myocardial infarction

Background

ST-segment elevation in the right-sided chest lead V₄R in inferior wall myocardial infarction is recognized as a sign of proximal occlusion of the right coronary artery with evolving right ventricular myocardial infarction. Our objective is to study how often lead V₄R is recorded in clinical practice and how this might be associated with use of reperfusion therapy and outcome of patients.

Methods

Recording of lead V₄R in 814 consecutive patients with acute myocardial infarction, administration of therapy, and outcome of the patients during a median follow-up of 285 days (174-313 days) were studied.

Results

V₄R was recorded in 52% of patients with inferior ST-elevation myocardial infarction. Patients with V₄R recorded were more likely to receive fibrinolytic therapy compared with patients without recording (65% vs 51%; P = .035). In multivariate analysis, recording of lead V₄R (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.1-2.2; P = .006), along with age (P < .001), previous myocardial infarction (OR 2.2, 95% CI 1.3-3.5; P = .002), and diabetes (OR 3.9, 95% CI 1.1-2.4; P = .03) correlated to the use of reperfusion therapy. Patients with lead V₄R recorded had less (P = .055) reinfarction, unstable angina, stroke, and/or death during follow-up.

Conclusions

Lead V₄R was recorded in only half of patients with inferior ST-elevation myocardial infarction. Patients with V₄R recorded were more likely to receive thrombolytic therapy than those without recording of the additional chest lead.     

Functioning and preferences for improvement of health among patients with juvenile idiopathic arthritis in early adulthood using the WHO ICF model

OBJECTIVE: To evaluate functioning and preferences for health among young adult patients with juvenile idiopathic arthritis (JIA) and controls. The WHO International Classification of Functioning, Disability and Health (ICF) was used as a framework. METHODS: The patient files of a rheumatology hospital were screened to identify patients with juvenile arthritis born 1976 to 1980. Functioning was measured by the Finnish version of the Multidimensional Health Assessment Questionnaire (MDHAQ) within the framework of the ICF. Preferences in improvement of health were measured by the Finnish version of the Arthritis Impact Measurement Scales 2. Age and sex matched controls from the community were selected from the Finnish population registry. RESULTS: In all, 123 patients with a mean age of 23 (SD 21-26) years participated in the followup study. The mean time from diagnosis to followup was 16.2 years. Among them, 35% (n = 43) were in remission at followup. Lower levels of functioning for 3 ICF components were found in patients with active disease compared to controls. JIA patients with active disease had more pain and lower levels of mobility, self-care, and domestic and social life compared to controls. Patients with active disease differed from those in remission with pain in preferences for improvement of health. CONCLUSION: Patients with active disease need active treatment and rehabilitation to maintain functioning and decrease pain. The ICF offers a promising model to examine the outcomes of adult patients with JIA. Application of the MDHAQ is supported by our evaluation studies in young adults with JIA.     

Insights into bear evolution from a Pleistocene polar bear genome

The polar bear (Ursus maritimus) has become a symbol of the threat to biodiversity from climate change. Understanding polar bear evolutionary history may provide insights into apex carnivore responses and prospects during periods of extreme environmental perturbations. In recent years, genomic studies have examined bear speciation and population history, including evidence for ancient admixture between polar bears and brown bears (Ursus arctos). Here, we extend our earlier studies of a 130,000- to 115,000-y-old polar bear from the Svalbard Archipelago using a 10× coverage genome sequence and 10 new genomes of polar and brown bears from contemporary zones of overlap in northern Alaska. We demonstrate a dramatic decline in effective population size for this ancient polar bear’s lineage, followed by a modest increase just before its demise. A slightly higher genetic diversity in the ancient polar bear suggests a severe genetic erosion over a prolonged bottleneck in modern polar bears. Statistical fitting of data to alternative admixture graph scenarios favors at least one ancient introgression event from brown bears into the ancestor of polar bears, possibly dating back over 150,000 y. Gene flow was likely bidirectional, but allelic transfer from brown into polar bear is the strongest detected signal, which contrasts with other published work. These findings may have implications for our understanding of climate change impacts: Polar bears, a specialist Arctic lineage, may not only have undergone severe genetic bottlenecks but also been the recipient of generalist, boreal genetic variants from brown bears during critical phases of Northern Hemisphere glacial oscillations.

The polar bear (Ursus maritimus) has become a symbolic species for ascertaining the impact of climate change on biodiversity and species evolution. With their dependence on sea ice, polar bears owe their continuing survival to the future stability of the vast Arctic regions of the planet. In connection, given Pleistocene oscillations between glacial and interglacial periods, polar bear paleohistory must hold clues to future responses to changing Earth climates. High-coverage genomes from ancient polar bear remains could therefore provide invaluable insights regarding prior adaptative resilience of the species to extreme environmental fluctuations in the past. Moreover, should such ancient polar bears be appropriately placed in age, their paleogenomes could illuminate the lineage split from the species’ lower-latitude sister taxon, the brown bear (Ursus arctos), in addition to enlightening any postdivergence admixture between the two species. However, polar bear fossils are very rare, with most dating to the Holocene period (1–3). In 2012 (4), extensive genomic data were generated from 23 extant polar bears, and a draft genome was presented from a stratigraphically validated 130,000- to 115,000-y-old polar bear jawbone of Eemian interglacial age that was recovered from the Svalbard Archipelago of Norway (1, 5). At the time, that study successfully pushed the age record of a sequenced vertebrate genome toward the Middle Pleistocene, but the initial draft genome was of low coverage (<1× depth), limiting its utility in genome-scale analyses.Several additional genomic studies have since sought to trace polar bear evolution, a species that has emerged for uncovering complex speciation processes associated with interspecific admixture and rapid evolutionary adaptation (6–10). Although the polar bear and brown bear are recognized as closely related yet highly distinct species, studies so far strongly point to ancient and even ongoing (11) introgressive hybridization between the two lineages. This work has mostly centered on polar bear admixture with brown bears in Alaska’s Alexander Archipelago, because mitochondrial haplotypes of brown bears in the archipelago today (the so-called ABC brown bears) are more similar to polar bear haplotypes than they are to haplotypes found in most non-ABC brown bears (3, 6, 12–14). The deep nesting of polar bears within the brown bear maternal lineage, along with the fact that several other, both modern and extinct, brown bear populations share mitochondrial haplotypes with polar bears (15–17), implies a much more complex evolutionary history beyond only the Alexander Archipelago. Indeed, analyses of bear nuclear genomes have suggested widespread allele sharing among polar bears and brown bears, including extinct Irish brown bears (7), albeit with the highest proportion of allele sharing found between polar bears and ABC brown bears (8, 9). The nature of this allele sharing has been interpreted to represent multiple polar bear introgressions into various brown bear lineages (7), but this directionality, although broadly accepted, is not conclusively established.Population genomic analyses have also identified an ancient and drastic decline in polar bear effective population size over the past 300,000 y, reflecting the far lower genetic diversity among extant polar bears compared to brown bears (4, 9). The complex population histories of the two sister species have challenged models for estimating divergence times and left a conundrum concerning the age of the polar bear as a species. Applying an extended coalescence hidden Markov model based on isolation with migration, an initial split time between brown and polar bears and American black bear (Ursus americanus) was estimated to be ∼5 to 4 Ma, followed by a period of gene flow before a complete split ∼200 ka (4). However, other estimates have generally agreed on a much younger split, although spanning a large interval from ∼1.6 Ma to 200 ka (9, 18).The complex model for polar bear evolution that suggests multiple introgression events from polar bear into brown bear (7) warrants further scrutiny with a more complete sampling of crucial North American brown bear populations and methodologies that permit explicit testing of alternative hypotheses of admixture directionality. Here, we present a 10× depth genome of the 130,000- to 115,000-y-old subfossil polar bear from the Norwegian Svalbard Archipelago and 10 new polar and brown bear genomes from contemporary zones of overlap in northern Alaska where the species may have come into increasing contact due to recent climatic changes. Using a more complete genome from this ancient polar bear and an extended sampling of extant bear populations, we compare 65 polar bear and brown bear genomes from throughout their geographic ranges to better characterize evolutionary splits and admixture between the species.     

Measuring the bioavailability of two hydrophobic organic compounds in the presence of dissolved organic matter

Bioavailability of benzo[a]pyrene (BaP) and 3,3',4,4'-tetrachlorobiphenyl (TCB) was studied in natural lake water containing dissolved organic matter (DOM). Lake water was diluted to give a dissolved organic carbon (DOC) range of 1 to 20 mg/L. Partition coefficients for the model compounds were assessed at different DOM concentrations and over time with three different methods, namely equilibrium dialysis and reverse-phase and liquid-liquid extraction. In addition, biological partition coefficients were estimated from the difference in the bioconcentration of the model compounds in Daphnia magna in the presence and absence of DOM. Results showed that bioavailability of the model compounds was reduced by the presence of DOM. The equilibrium dialysis method gave the best estimates for bioavailability of the model compounds when compared with biologically determined values. Both the reverse-phase and the liquid-liquid extraction overestimated the bioavailable fraction. The more pronounced overestimation of bioavailable fraction of TCB suggested that the sorption of TCB was not only lower but the interaction was also weaker than that of BaP. Increasing DOM concentration produced lower partition coefficients and the effect seemed to be more pronounced when measured by the reverse-phase and the extraction methods.     

Intraputamenal Cerebral Dopamine Neurotrophic Factor in Parkinson's Disease: A Randomized,Double-Blind,Multicenter Phase 1 Trial

Background

Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that protects dopamine neurons and improves motor function in animal models of Parkinson's disease (PD).

Objective

The primary objectives of this study were to assess the safety and tolerability of both CDNF and the drug delivery system (DDS) in patients with PD of moderate severity.

Methods

We assessed the safety and tolerability of monthly intraputamenal CDNF infusions in patients with PD using an investigational DDS, a bone-anchored transcutaneous port connected to four catheters. This phase 1 trial was divided into a placebo-controlled, double-blind, 6-month main study followed by an active-treatment 6-month extension. Eligible patients, aged 35 to 75 years, had moderate idiopathic PD for 5 to 15 years and Hoehn and Yahr score ≤ 3 (off state). Seventeen patients were randomized to placebo (n = 6), 0.4 mg CDNF (n = 6), or 1.2 mg CDNF (n = 5). The primary endpoints were safety and tolerability of CDNF and DDS and catheter implantation accuracy. Secondary endpoints were measures of PD symptoms, including Unified Parkinson's Disease Rating Scale, and DDS patency and port stability. Exploratory endpoints included motor symptom assessment (PKG, Global Kinetics Pty Ltd, Melbourne, Australia) and positron emission tomography using dopamine transporter radioligand [¹⁸F]FE-PE2I.

Results

Drug-related adverse events were mild to moderate with no difference between placebo and treatment groups. No severe adverse events were associated with the drug, and device delivery accuracy met specification. The severe adverse events recorded were associated with the infusion procedure and did not reoccur after procedural modification. There were no significant changes between placebo and CDNF treatment groups in secondary endpoints between baseline and the end of the main and extension studies.

Conclusions

Intraputamenally administered CDNF was safe and well tolerated, and possible signs of biological response to the drug were observed in individual patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.