Nickel complexes of phosphine-appended benzannulated boron heterocycles

We report the synthesis and characterization of two diphosphine nickel complexes containing 9-borafluorene (PBFlu, 9-(diisopropylphosphino)phenyl-9-borafluorene) and 9,10-dihydroboranthrene (B 2 P 2 , 9,10-bis(2-(diisopropylphosphino)phenyl)-9,10-dihydroboranthrene) cores. Metalation of PBFlu and B 2 P 2 with Ni(PPh 3 ) 4 leads to the monometallic complexes (PBFlu)Ni(PPh 3 ) and (B 2 P 2 )Ni, respectively. Cyclic voltammetry studies show a reversible redox event at ∼0.1 V and a quasi-reversible event at ca. −3 V versus ferrocene/ferrocenium for (B 2 P 2 )Ni while (PBFlu)Ni(PPh 3 ) features no reversible redox events. Electronic structure calculations were performed to provide further insight into the bonding in these complexes

Experimental glomerulonephritis induced by hydrocarbon exposure: A systematic review

BACKGROUND: Much epidemiological evidence suggests that hydrocarbon exposure may induce glomerulonephritis and worsen its course in many patients. The mechanisms are unknown, however, no specific microscopic pattern has been identified, and it has also been argued that hydrocarbon exposure causes tubular damage mainly. Studying experimental animals may best answer these questions, and as no systematic review of glomerulonephritis produced experimentally by hydrocarbon exposure has been performed previously, I found it relevant to search for and analyse such studies. METHODS: Animal experiments having mimicked human glomerulonephritis by hydrocarbon exposure were sought on Medline and Toxnet RESULTS: Twenty-six experiments using thirteen different hydrocarbons were identified. Several human subtypes were observed including IgA nephritis, mesangial, proliferative and extracapillary glomerulonephritis, focal and focal-segmental sclerosis, minimal change nephropathy, anti-GBM and anti-TBM nephritis, and glomerulonephritis associated with peiarteritis nodosa. Glomerular proteinuria was seen in 10/12 experiments that included urine analyses, and renal failure in 5/8 experiments that included measurements of glomerular function. All experiments resulted in various degrees of tubular damage as well. In most studies, where the animals were examined at different times during or after the exposure, the renal microscopic and functional changes were seen immediately, whereas deposits of complement and immunoglobulins appeared late in the course, if at all. CONCLUSION: These experiments are in accord with epidemiological evidence that hydrocarbon exposure may cause glomerulonephritis and worsen renal function. Probable mechanisms include an induction of autologous antibodies and a disturbance of normal immunological functions. Also, tubular damage may increase postglomerular resistance, resulting in a glomerular deposition of macromolecules. In most models a causal role of glomerular immune complex formation was unlikely, but may rather have been a secondary phenomenon. As most glomerulonephritis subgroups were seen and as some of the hydrocarbons produced more than one subgroup, the microscopic findings in a patient cannot be used as a clue to the causation of his disease. By the same reason, the lack of a specific histological pattern in patients with glomerulonephritis assumed to have been caused by hydrocarbon exposure is not contradictive

Translating the potential of the urine steroid metabolome to stage NAFLD (TrUSt-NAFLD): study protocol for a multicentre, prospective validation study.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) affects approximately one in four individuals and its prevalence continues to rise. The advanced stages of NAFLD with significant liver fibrosis are associated with adverse morbidity and mortality outcomes. Currently, liver biopsy remains the 'gold-standard' approach to stage NAFLD severity. Although generally well tolerated, liver biopsies are associated with significant complications, are resource intensive, costly, and sample only a very small area of the liver as well as requiring day case admission to a secondary care setting. As a result, there is a significant unmet need to develop non-invasive biomarkers that can accurately stage NAFLD and limit the need for liver biopsy. The aim of this study is to validate the use of the urine steroid metabolome as a strategy to stage NAFLD severity and to compare its performance against other non-invasive NAFLD biomarkers. METHODS AND ANALYSIS: The TrUSt-NAFLD study is a multicentre prospective test validation study aiming to recruit 310 patients with biopsy-proven and staged NAFLD across eight centres within the UK. 150 appropriately matched control patients without liver disease will be recruited through the Oxford Biobank. Blood and urine samples, alongside clinical data, will be collected from all participants. Urine samples will be analysed by liquid chromatography-tandem mass spectroscopy to quantify a panel of predefined steroid metabolites. A machine learning-based classifier, for example, Generalized Matrix Relevance Learning Vector Quantization that was trained on retrospective samples, will be applied to the prospective steroid metabolite data to determine its ability to identify those patients with advanced, as opposed to mild-moderate, liver fibrosis as a consequence of NAFLD. ETHICS AND DISSEMINATION: Research ethical approval was granted by West Midlands, Black Country Research Ethics Committee (REC reference: 21/WM/0177). A substantial amendment (TrUSt-NAFLD-SA1) was approved on 26 November 2021. TRIAL REGISTRATION NUMBER: ISRCTN19370855

Splenectomy for solitary splenic metastasis of ovarian cancer

BACKGROUND: Splenic metastases occur in rare cases with a few case reports of patients in the literature. Generally, splenic metastases mean late dissemination of a disease. Solitary splenic metastases from solid tumors are extremely unusual. CASE PRESENTATION: We report a case of a patient with ovarian mucinous cystadenocarcinoma who underwent splenectomy for isolated parenchymal metastasis. CONCLUSION: Ovarian epithelial tumors comprised most of isolated splenic metastases from gynecologic tumor. When isolated splenic recurrence is suspected on image studies and serum tumor markers, intraabdominal gross findings should be examined to exclude peritoneal carcinomatosis. If only spleen was under suspicion of recurrence of ovarian cancer, splenectomy may play a therapeutic role

Mitochondrial complex 1 activity measured by spectrophotometry is reduced across all brain regions in ageing and more specifically in neurodegeneration

Mitochondrial function, in particular complex 1 of the electron transport chain (ETC), has been shown to decrease during normal ageing and in neurodegenerative disease. However, there is some debate concerning which area of the brain has the greatest complex 1 activity. It is important to identify the pattern of activity in order to be able to gauge the effect of age or disease related changes. We determined complex 1 activity spectrophotometrically in the cortex, brainstem and cerebellum of middle aged mice (70–71 weeks), a cerebellar ataxic neurodegeneration model (pcd5J) and young wild type controls. We share our updated protocol on the measurements of complex1 activity and find that mitochondrial fractions isolated from frozen tissues can be measured for robust activity. We show that complex 1 activity is clearly highest in the cortex when compared with brainstem and cerebellum (p<0.003). Cerebellum and brainstem mitochondria exhibit similar levels of complex 1 activity in wild type brains. In the aged brain we see similar levels of complex 1 activity in all three-brain regions. The specific activity of complex 1 measured in the aged cortex is significantly decreased when compared with controls (p<0.0001). Both the cerebellum and brainstem mitochondria also show significantly reduced activity with ageing (p<0.05). The mouse model of ataxia predictably has a lower complex 1 activity in the cerebellum, and although reductions are measured in the cortex and brain stem, the remaining activity is higher than in the aged brains. We present clear evidence that complex 1 activity decreases across the brain with age and much more specifically in the cerebellum of the pcd5j mouse. Mitochondrial impairment can be a region specific phenomenon in disease, but in ageing appears to affect the entire brain, abolishing the pattern of higher activity in cortical regions

Intra-Organ Variation in Age-Related Mutation Accumulation in the Mouse

Using a transgenic mouse model harboring chromosomally integrated lacZ mutational target genes, we previously demonstrated that mutations accumulate with age much more rapidly in the small intestine than in the brain. Here it is shown that in the small intestine point mutations preferentially accumulate in epithelial cells of the mucosa scraped off the underlying serosa. The mucosal cells are the differentiated villus cells that have undergone multiple cell divisions. A smaller age-related increase, also involving genome rearrangements, was observed in the serosa, which consists mainly of the remaining crypts and non-dividing smooth muscle cells. In the brain we observed an accumulation of only point mutations in no other areas than hypothalamus and hippocampus. To directly test for cell division as the determining factor in the generation of point mutations we compared mutation induction between mitotically active and quiescent embryonic fibroblasts from the same lacZ mice, treated with either UV (a point mutagen) or hydrogen peroxide (a clastogen). The results indicate that while point mutations are highly replication-dependent, genome rearrangements are as easily induced in non-dividing cells as in mitotically active ones. This strongly suggests that the point mutations found to have accumulated in the mucosal part of the small intestine are the consequence of replication errors. The same is likely true for point mutations accumulating in hippocampus and hypothalamus of the brain since neurogenesis in these two areas continues throughout life. The observed intra-organ variation in mutation susceptibility as well as the variation in replication dependency of different types of mutations indicates the need to not only extend observations made on whole organs to their sub-structures but also take the type of mutations and mitotic activity of the cells into consideration. This should help elucidating the impact of genome instability and its consequences on aging and disease

Does Non-Moral Ignorance Exculpate? Situational Awareness and Attributions of Blame and Forgiveness

In this paper, we set out to test empirically an idea that many philosophers find intuitive, namely that non-moral ignorance can exculpate. Many philosophers find it intuitive that moral agents are responsible only if they know the particular facts surrounding their action. Our results show that whether moral agents are aware of the facts surrounding their action does have an effect on people’s attributions of blame, regardless of the consequences or side effects of the agent’s actions. In general, it was more likely that a situationally aware agent will be blamed for failing to perform the obligatory action than a situationally unaware agent. We also tested attributions of forgiveness in addition to attributions of blame. In general, it was less likely that a situationally aware agent will be forgiven for failing to perform the obligatory action than a situationally unaware agent. When the agent is situationally unaware, it is more likely that the agent will be forgiven than blamed. We argue that these results provide some empirical support for the hypothesis that there is something intuitive about the idea that non-moral ignorance can exculpate

The effect of temperature, gradient and load carriage on oxygen consumption, posture and gait characteristics

Purpose The purpose of this experiment was to evaluate the effect of load carriage in a range of temperatures to establish the interaction between cold exposure, the magnitude of change from unloaded to loaded walking and gradient. Methods Eleven participants (19-27 years) provided written informed consent before performing six randomly ordered walking trials in six temperatures (20°C, 10°C, 5°C, 0°C, -5°C and -10°C). Trials involved two unloaded walking bouts before and after loaded walking (18.2 kg) at 4 km.hr⁻¹, on 0% and 10% gradients in 4 minute bouts. Results The change in absolute oxygen consumption (V̇O₂) from the first unloaded bout to loaded walking was similar across all six temperatures. When repeating the second unloaded bout, V̇O₂ at both -5°C and-10°C was greater compared to the first. At -10°C, V̇O₂ was increased from 1.60 ± 0.30 L.min⁻¹ to 1.89 ± 0.51 L.min⁻¹. Regardless of temperature, gradient had a greater effect on V̇O₂ and heart rate (HR) than backpack load. HR was unaffected by temperature. Stride length (SL) decreased with decreasing temperature but trunk forward lean was greater during cold exposure. Conclusion Decreased ambient temperature did not influence the magnitude of change in V̇O₂ from unloaded to loaded walking. However, in cold temperatures, V̇O₂ was significantly higher than in warm conditions. The increased V̇O₂ in colder temperatures at the same exercise intensity is predicted to ultimately lead to earlier onset of fatigue and cessation of exercise. These results highlight the need to consider both appropriate clothing and fitness during cold exposure

Constructing an index of physical fitness age for Japanese elderly based on 7-year longitudinal data: sex differences in estimated physical fitness age

A standardized method for assessing the physical fitness of elderly adults has not yet been established. In this study, we developed an index of physical fitness age (fitness age score, FAS) for older Japanese adults and investigated sex differences based on the estimated FAS. Healthy elderly adults (52 men, 70 women) who underwent physical fitness tests once yearly for 7 years between 2002 and 2008 were included in this study. The age of the participants at the beginning of this study ranged from 60.0 to 83.0 years. The physical fitness tests consisted of 13 items to measure balance, agility, flexibility, muscle strength, and endurance. Three criteria were used to evaluate fitness markers of aging: (1) significant cross-sectional correlation with age; (2) significant longitudinal change with age consistent with the cross-sectional correlation; and (3) significant stability of individual differences. We developed an equation to assess individual FAS values using the first principal component derived from principal component analysis. Five candidate fitness markers of aging (10-m walking time, functional reach, one leg stand with eyes open, vertical jump and grip strength) were selected from the 13 physical fitness tests. Individual FAS was predicted from these five fitness markers using a principal component model. Individual FAS showed high longitudinal stability for age-related changes. This investigation of the longitudinal changes of individual FAS revealed that women had relatively lower physical fitness compared with men, but their rate of physical fitness aging was slower than that of men

Predicting Diabetic Nephropathy Using a Multifactorial Genetic Model

AIMS: The tendency to develop diabetic nephropathy is, in part, genetically determined, however this genetic risk is largely undefined. In this proof-of-concept study, we tested the hypothesis that combined analysis of multiple genetic variants can improve prediction. METHODS: Based on previous reports, we selected 27 SNPs in 15 genes from metabolic pathways involved in the pathogenesis of diabetic nephropathy and genotyped them in 1274 Ashkenazi or Sephardic Jewish patients with Type 1 or Type 2 diabetes of >10 years duration. A logistic regression model was built using a backward selection algorithm and SNPs nominally associated with nephropathy in our population. The model was validated by using random "training" (75%) and "test" (25%) subgroups of the original population and by applying the model to an independent dataset of 848 Ashkenazi patients. RESULTS: The logistic model based on 5 SNPs in 5 genes (HSPG2, NOS3, ADIPOR2, AGER, and CCL5) and 5 conventional variables (age, sex, ethnicity, diabetes type and duration), and allowing for all possible two-way interactions, predicted nephropathy in our initial population (C-statistic = 0.672) better than a model based on conventional variables only (C = 0.569). In the independent replication dataset, although the C-statistic of the genetic model decreased (0.576), it remained highly associated with diabetic nephropathy (χ(2) = 17.79, p<0.0001). In the replication dataset, the model based on conventional variables only was not associated with nephropathy (χ(2) = 3.2673, p = 0.07). CONCLUSION: In this proof-of-concept study, we developed and validated a genetic model in the Ashkenazi/Sephardic population predicting nephropathy more effectively than a similarly constructed non-genetic model. Further testing is required to determine if this modeling approach, using an optimally selected panel of genetic markers, can provide clinically useful prediction and if generic models can be developed for use across multiple ethnic groups or if population-specific models are required