To evaluate the efficacy of dichloroacetate (DCA) in the treatment of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS).
High levels of ventricular lactate, the ...brain spectroscopic signature of MELAS, correlate with more severe neurologic impairment. The authors hypothesized that chronic cerebral lactic acidosis exacerbates neuronal injury in MELAS and therefore, investigated DCA, a potent lactate-lowering agent, as potential treatment for MELAS.
The authors conducted a double-blind, placebo-controlled, randomized, 3-year cross-over trial of DCA (25 mg/kg/day) in 30 patients (aged 10 to 60 years) with MELAS and the A3243G mutation. Primary outcome measure was a Global Assessment of Treatment Efficacy (GATE) score based on a health-related event inventory, and on neurologic, neuropsychological, and daily living functioning. Biologic outcome measures included venous, CSF, and 1H MRSI-estimated brain lactate. Blood tests and nerve conduction studies were performed to monitor safety.
During the initial 24-month treatment period, 15 of 15 patients randomized to DCA were taken off study medication, compared to 4 of 15 patients randomized to placebo. Study medication was discontinued in 17 of 19 patients because of onset or worsening of peripheral neuropathy. The clinical trial was terminated early because of peripheral nerve toxicity. The mean GATE score was not significantly different between treatment arms.
DCA at 25 mg/kg/day is associated with peripheral nerve toxicity resulting in a high rate of medication discontinuation and early study termination. Under these experimental conditions, the authors were unable to detect any beneficial effect. The findings show that DCA-associated neuropathy overshadows the assessment of any potential benefit in MELAS.
This paper presents three maps that summarize current knowledge as to the extent of Past permafrost and Relict permafrost in North America at approximately the time of the Last Glacial Maximum (LGM; ...c. 25–17 ka BP) and during subsequent deglaciation until c. 10 ka BP. Analysis of the post‐1983 literature suggests that the extent of Past permafrost south of the LGM limit was broader in eastern North America and slightly narrower in the Interior Great Plains than previously mapped. The recognition and dating of Relict permafrost in the nonglaciated terrain of the northwestern Arctic suggests that permafrost may be of great antiquity and can persist under changing climatic conditions. The formation of permafrost features during deglaciation suggests that ice‐proximal climatic conditions remained cold at least long enough for short‐lived permafrost aggradation; a latitudinal gradient is evident in the timing of its development as the Laurentide Ice Sheet retreated.
In this essay we examine the case of Kivalina, Alaska, twice threatened with destruction, in order to understand the importance of the specifically geological concept of the Anthropocene. We argue ...that the Anthropocene is best understood as part of what Neil Smith called a “tight dialectic” between the history of geography (the production of environmental knowledge) and historical geography (the production of nature and space) as this dialectic is played out within capitalist modes of production. We focus on the relationship between contemporary geo‐engineering and both intentional and unintentional geographical engineering, to make the basic argument that humans have no choice but to produce nature—to engineer environments. The only question is how we shall do so.
The European flat oyster Ostrea edulis once settled in high densities throughout its natural range but now exists only in small fragmented populations. In the Sea Lough of Strangford, Northern ...Ireland, recent increases in intertidal oyster numbers at historical sites along the north-east shore were recorded in 2018. A substantial number of conjoined oyster settlements were recorded within this density increase. One intertidal site produced numerous three-dimensional (3D) O. edulis specific matrices containing >16 oysters. In contrast, an extensive search of post and pre-1700s literature uncovered relatively few accounts of species-specific 3D O. edulis matrices and none relating to intertidal populations. The gregarious 3D settlements discovered during this research represent the first documented evidence of the phenomenon in Ireland. These emergent native oyster reef structures offer an insight into the possible intertidal O. edulis formations, which existed pre-1700 and could act as a guide to what may still be obtainable in the future.
•First records of extant Ostrea edulis 3D matrices in Ireland.•Evidence of O. edulis reef formations in European archives.•Native oyster settlement in conjoined formations; emergent reef or beds.
Patients with non-specific symptoms often experience longer times to diagnosis and poorer clinical outcomes than those with site-specific symptoms. This paper reports initial results from five ...multidisciplinary diagnostic centre (MDC) projects in England, piloting rapid referral for patients with non-specific symptoms.
The evaluation covered MDC activity from 1st December 2016 to 31st July 2018, with projects using a common dataset. Logistical regression analyses were conducted, with a diagnosis of any cancer as the dependent variable. Exploratory analysis was conducted on presenting symptoms and diagnoses of cancer, and on comparisons within these groupings.
In total, 2961 patients were referred into the MDCs and 241 cancers were diagnosed. The pathway detected cancers across a broad range of tumour sites, including several rare and less common cancers. An association between patient age and cancer was identified (p < 0.001). GP 'clinical suspicion' was identified as a strong predictor of cancer (p = 0.006), with a reduced association with cancer observed in patients with higher numbers of GP consultation before referral (p = 0.008).
The MDC model diagnoses cancer in patients with non-specific symptoms, with a conversion rate of 8%, demonstrating the diagnostic potential of a non-site-specific symptomatic referral pathway.
A balanced t(1;11) translocation that transects the Disrupted in schizophrenia 1 (DISC1) gene shows genome-wide significant linkage for schizophrenia and recurrent major depressive disorder (rMDD) in ...a single large Scottish family, but genome-wide and exome sequencing-based association studies have not supported a role for DISC1 in psychiatric illness. To explore DISC1 in more detail, we sequenced 528 kb of the DISC1 locus in 653 cases and 889 controls. We report 2718 validated single-nucleotide polymorphisms (SNPs) of which 2010 have a minor allele frequency of <1%. Only 38% of these variants are reported in the 1000 Genomes Project European subset. This suggests that many DISC1 SNPs remain undiscovered and are essentially private. Rare coding variants identified exclusively in patients were found in likely functional protein domains. Significant region-wide association was observed between rs16856199 and rMDD (P=0.026, unadjusted P=6.3 × 10(-5), OR=3.48). This was not replicated in additional recurrent major depression samples (replication P=0.11). Combined analysis of both the original and replication set supported the original association (P=0.0058, OR=1.46). Evidence for segregation of this variant with disease in families was limited to those of rMDD individuals referred from primary care. Burden analysis for coding and non-coding variants gave nominal associations with diagnosis and measures of mood and cognition. Together, these observations are likely to generalise to other candidate genes for major mental illness and may thus provide guidelines for the design of future studies.
OBJECTIVE: To identify which psychological and psychosocial constructs to include in a core outcome set to guide future clinical trials in the tendinopathy field. DESIGN: Modified International ...Delphi study. METHODS: In 3 online Delphi rounds, we presented 35 psychological and psychosocial constructs to an international panel of 38 clinician/researchers and people with tendinopathy. Using a 9-point Likert scale (1 = not important to include, 9 = critical to include), consensus for construct inclusion required ≥70% of respondents rating "extremely critical to include" (score ≥7) and ≤15% rating "not important to include" (score ≤3). Consensus for exclusion required ≥70% of respondents rating "not important to include" (score ≤3) and ≤15% of rating "critical to include" (score ≥7). RESULTS: Thirty-six participants (95% of 38) completed round 1, 90% (n = 34) completed round 2, and 87% (n = 33) completed round 3. Four constructs were deemed important to include as part of a core outcome set: kinesiophobia (82%, median: 8, interquartile range IQR: 1.0), pain beliefs (76%, median: -7, IQR: 1.0), pain-related self-efficacy (71%, median: 7, IQR: 2.0), and fear-avoidance beliefs (73%, median: -7, IQR: 1.0). Six constructs were deemed not important to include: perceived injustice (82%), individual attitudes of family members (74%), social isolation and loneliness (73%), job satisfaction (73%), coping (70%), and educational attainment (70%). Clinician/researchers and people with tendinopathy reached consensus that kinesiophobia, pain beliefs, pain self-efficacy, and fear-avoidance beliefs were important psychological constructs to measure in tendinopathy clinical trials. J Orthop Sports Phys Ther 2024;54(1):1-12. Epub 20 September 2023. doi:10.2519/jospt.2023.11903.
Ostrea edulis was once prolific throughout Europe and considered as the continent's native oyster. However, O. edulis currently exists in small fragmented assemblages where natural unaided recovery ...is rarely encountered. This research identified the small semi‐enclosed sea Lough of Strangford on the northeast coast of Northern Ireland as one of the few locations within Europe where the native oyster displayed gregarious natural rejuvenation. On close examination, four influential parameters appeared to assist in concentrated settlement; raised topographical cultch formations, shell coverage, the number of fecund in situ adults, and site protection. If these components were to be combined and managed as part of reintroduction and restoration initiatives, high‐density settlements and self‐sustaining populations may be possible. The research also identified that unregulated harvesting of intertidal O. edulis assemblages has the potential to seriously hinder natural recoveries. Indeed, the findings suggest that a review of policy in regards to intertidal hand gathering is necessary. However, naturally occurring high‐density settlements recorded during this research should be inspirational to all involved in the restoration of the native oyster.
Background: Myopericytoma (MPC) is a recently proposed term to describe a group of tumours that originate from perivascular myoid cells and show a range of histological growth patterns. Only a small ...number of series describing MPC have been reported. MPC is frequently misdiagnosed as a sarcoma. Aims: To document the clinical and histopathological findings of a series of MPCs, to describe the range of growth patterns and morphological spectrum, and to compare MPC with myofibroma (MF). Patients/Methods: Fourteen patients with features of MPC and/or MF were identified from the archival files of the department of anatomical pathology, Royal Prince Alfred Hospital, Sydney, Australia. Results: There were six female and eight male patients. The mean and median patient ages were 37 and 35.5 years, respectively. The tumours were located in the skin, subcutis, or superficial soft tissues of the distal extremities (13 patients) or the head and neck region (one patient), and showed a spectrum of morphological appearances. They were divided into two groups based upon the predominant growth pattern corresponding to MPC (seven cases) and MF (seven cases). The feature most suggestive of MPC was the presence of a concentric perivascular arrangement of plump spindle shaped cells. The presence of a zonation/biphasic appearance was most characteristic of MF. Conclusions: MPC exhibits a spectrum of growth patterns that overlap with MF. Tumours can be designated as MPC or MF depending on the predominant growth pattern.
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